Editorial

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Open AccessEditorial

Comments about the IJMS Special Issue: Molecular Interactions and Mechanisms of COVID-19 Inhibition

by Francesco Caruso and Miriam Rossi

Int. J. Mol. Sci. 2022, 23(17), 9607; https://doi.org/10.3390/ijms23179607 - 25 Aug 2022

Viewed by 982

Abstract

The unprecedented COVID-19 pandemic showed up during the latter part of 2019 in Wuhan, China [...] Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

Research

Jump to: Editorial, Review

15 pages, 1850 KiB

Open AccessArticle

Angiotensin II Exaggerates SARS-CoV-2 Specific T-Cell Response in Convalescent Individuals following COVID-19

by Moudhi Almutlaq, Fatmah A. Mansour, Jahad Alghamdi, Yassen Alhendi, Abir Abdullah Alamro, Amani Ahmed Alghamdi, Hassan S. Alamri, Fayhan Alroqi and Tlili Barhoumi

Int. J. Mol. Sci. 2022, 23(15), 8669; https://doi.org/10.3390/ijms23158669 - 04 Aug 2022

Cited by 9 | Viewed by 1686

Abstract

Dysregulation of renin−angiotensin systems during coronavirus disease 2019 (COVID-19) infection worsens the symptoms and contributes to COVID-19 severity and mortality. This study sought to investigate the effect of exogenous angiotensin II (Ang-II) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cells response in [...] Read more.

Dysregulation of renin−angiotensin systems during coronavirus disease 2019 (COVID-19) infection worsens the symptoms and contributes to COVID-19 severity and mortality. This study sought to investigate the effect of exogenous angiotensin II (Ang-II) on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cells response in recovered COVID-19 patients. Human peripheral blood mononuclear cells (PBMCs) were treated with Ang II and then stimulated with a SARS-CoV-2 peptide pool. T-cell responses were measured using flow cytometry, while enzyme-linked immunosorbent assay (ELISA) and intracellular cytokine staining (ICS) assays determined functional capability and polarization. Additionally, the relative level of protein phosphorylation was measured using a phosphokinase array. Our results showed that Ang II treatment significantly increased the magnitude of SARS-CoV-2-specific T-cell response in stimulated PBMCs with a SARS-CoV-2 peptide pool. Moreover, the phosphorylation levels of numerous proteins implicated in cardiovascular diseases, inflammation, and viral infection showed significant increases in the presence of Ang II. The mitogenic stimulation of PBMCs after Ang II and SARS-CoV-2 peptide pool stimulation showed functional polarization of T-cells toward Th1/Th17 and Th17 phenotypes, respectively. Meanwhile, ELISA showed increased productions of IL-1β and IL-6 in Ang II-stimulated PBMCs without affecting the IL-10 level. To our knowledge, this study is the first to demonstrate that Ang II exaggerates SARS-CoV-2-specific T-cells response. Therefore, during COVID-19 infection, Ang II may aggravate the inflammatory response and change the immune response toward a more inflammatory profile against SARS-CoV-2 infection. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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19 pages, 31359 KiB

Open AccessArticle

D,L-Lysine-Acetylsalicylate + Glycine (LASAG) Reduces SARS-CoV-2 Replication and Shows an Additive Effect with Remdesivir

by Johannes Jungwirth, Clio Häring, Sarah König, Liane Giebeler, Heena Doshi, Christian Brandt, Stefanie Deinhardt-Emmer, Bettina Löffler and Christina Ehrhardt

Int. J. Mol. Sci. 2022, 23(13), 6880; https://doi.org/10.3390/ijms23136880 - 21 Jun 2022

Cited by 1 | Viewed by 3064

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease-19 (COVID-19) is still challenging healthcare systems and societies worldwide. While vaccines are available, therapeutic strategies are developing and need to be adapted to each patient. Many clinical approaches focus on the [...] Read more.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing the coronavirus disease-19 (COVID-19) is still challenging healthcare systems and societies worldwide. While vaccines are available, therapeutic strategies are developing and need to be adapted to each patient. Many clinical approaches focus on the repurposing of approved therapeutics against other diseases. However, the efficacy of these compounds on viral infection or even harmful secondary effects in the context of SARS-CoV-2 infection are sparsely investigated. Similarly, adverse effects of commonly used therapeutics against lifestyle diseases have not been studied in detail. Using mono cell culture systems and a more complex chip model, we investigated the effects of the acetylsalicylic acid (ASA) salt D,L-lysine-acetylsalicylate + glycine (LASAG) on SARS-CoV-2 infection in vitro. ASA is commonly known as Aspirin^® and is one of the most frequently used medications worldwide. Our data indicate an inhibitory effect of LASAG on SARS-CoV-2 replication and SARS-CoV-2-induced expression of pro-inflammatory cytokines and coagulation factors. Remarkably, our data point to an additive effect of the combination of LASAG and the antiviral acting drug remdesivir on SARS-CoV-2 replication in vitro. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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14 pages, 2528 KiB

Open AccessArticle

Atomistic-Level Description of the Covalent Inhibition of SARS-CoV-2 Papain-like Protease

by Cécilia Hognon, Marco Marazzi and Cristina García-Iriepa

Int. J. Mol. Sci. 2022, 23(10), 5855; https://doi.org/10.3390/ijms23105855 - 23 May 2022

Cited by 6 | Viewed by 2153

Abstract

Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro [...] Read more.

Inhibition of the papain-like protease (PLpro) of SARS-CoV-2 has been demonstrated to be a successful target to prevent the spreading of the coronavirus in the infected body. In this regard, covalent inhibitors, such as the recently proposed VIR251 ligand, can irreversibly inactivate PLpro by forming a covalent bond with a specific residue of the catalytic site (Cys¹¹¹), through a Michael addition reaction. An inhibition mechanism can therefore be proposed, including four steps: (i) ligand entry into the protease pocket; (ii) Cys¹¹¹ deprotonation of the thiol group by a Brønsted–Lowry base; (iii) Cys¹¹¹-S⁻ addition to the ligand; and (iv) proton transfer from the protonated base to the covalently bound ligand. Evaluating the energetics and PLpro conformational changes at each of these steps could aid the design of more efficient and selective covalent inhibitors. For this aim, we have studied by means of MD simulations and QM/MM calculations the whole mechanism. Regarding the first step, we show that the inhibitor entry in the PLpro pocket is thermodynamically favorable only when considering the neutral Cys¹¹¹, that is, prior to the Cys¹¹¹ deprotonation. For the second step, MD simulations revealed that His²⁷² would deprotonate Cys¹¹¹ after overcoming an energy barrier of ca. 32 kcal/mol (at the QM/MM level), but implying a decrease of the inhibitor stability inside the protease pocket. This information points to a reversible Cys¹¹¹ deprotonation, whose equilibrium is largely shifted toward the neutral Cys¹¹¹ form. Although thermodynamically disfavored, if Cys¹¹¹ is deprotonated in close proximity to the vinylic carbon of the ligand, then covalent binding takes place in an irreversible way (third step) to form the enolate intermediate. Finally, due to Cys¹¹¹-S⁻ negative charge redistribution over the bound ligand, proton transfer from the initially protonated His²⁷² is favored, finally leading to an irreversibly modified Cys¹¹¹ and a restored His²⁷². These results elucidate the selectivity of Cys¹¹¹ to enable formation of a covalent bond, even if a weak proton acceptor is available, as His²⁷². Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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16 pages, 4328 KiB

Open AccessArticle

Drug-Free Nasal Spray as a Barrier against SARS-CoV-2 and Its Delta Variant: In Vitro Study of Safety and Efficacy in Human Nasal Airway Epithelia

by Fabio Fais, Reda Juskeviciene, Veronica Francardo, Stéphanie Mateos, Manuela Guyard, Cécile Viollet, Samuel Constant, Massimo Borelli and Ilja P. Hohenfeld

Int. J. Mol. Sci. 2022, 23(7), 4062; https://doi.org/10.3390/ijms23074062 - 06 Apr 2022

Cited by 9 | Viewed by 4739

Abstract

The nasal epithelium is a key portal for infection by respiratory viruses such as SARS-CoV-2 and represents an important target for prophylactic and therapeutic interventions. In the present study, we test the safety and efficacy of a newly developed nasal spray (AM-301, marketed [...] Read more.

The nasal epithelium is a key portal for infection by respiratory viruses such as SARS-CoV-2 and represents an important target for prophylactic and therapeutic interventions. In the present study, we test the safety and efficacy of a newly developed nasal spray (AM-301, marketed as Bentrio) against infection by SARS-CoV-2 and its Delta variant on an in vitro 3D-model of the primary human nasal airway epithelium. Safety was assessed in assays for tight junction integrity, cytotoxicity and cilia beating frequency. Efficacy against SARS-CoV-2 infection was evaluated in pre-viral load and post-viral load application on airway epithelium. No toxic effects of AM-301 on the nasal epithelium were found. Prophylactic treatment with AM-301 significantly reduced viral titer vs. controls over 4 days, reaching a maximum reduction of 99% in case of infection from the wild-type SARS-CoV-2 variant and more than 83% in case of the Delta variant. When AM-301 administration was started 24 h after infection, viral titer was reduced by about 12-folds and 3-folds on Day 4. The results suggest that AM-301 is safe and significantly decelerates SARS-CoV-2 replication in cell culture inhibition assays of prophylaxis (pre-viral load application) and mitigation (post-viral load application). Its physical (non-pharmaceutical) mechanism of action, safety and efficacy warrant additional investigations both in vitro and in vivo for safety and efficacy against a broad spectrum of airborne viruses and allergens. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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21 pages, 4499 KiB

Open AccessArticle

Mechanism of Caspase-1 Inhibition by Four Anti-inflammatory Drugs Used in COVID-19 Treatment

by Francesco Caruso, Jens Z. Pedersen, Sandra Incerpi, Sarjit Kaur, Stuart Belli, Radu-Mihai Florea and Miriam Rossi

Int. J. Mol. Sci. 2022, 23(3), 1849; https://doi.org/10.3390/ijms23031849 - 06 Feb 2022

Cited by 6 | Viewed by 4439

Abstract

The inflammatory protease caspase-1 is associated with the release of cytokines. An excessive number of cytokines (a “cytokine storm”) is a dangerous consequence of COVID-19 infection and has been indicated as being among the causes of death by COVID-19. The anti-inflammatory drug colchicine [...] Read more.

The inflammatory protease caspase-1 is associated with the release of cytokines. An excessive number of cytokines (a “cytokine storm”) is a dangerous consequence of COVID-19 infection and has been indicated as being among the causes of death by COVID-19. The anti-inflammatory drug colchicine (which is reported in the literature to be a caspase-1 inhibitor) and the corticosteroid drugs, dexamethasone and methylprednisolone, are among the most effective active compounds for COVID-19 treatment. The SERM raloxifene has also been used as a repurposed drug in COVID-19 therapy. In this study, inhibition of caspase-1 by these four compounds was analyzed using computational methods. Our aim was to see if the inhibition of caspase-1, an important biomolecule in the inflammatory response that triggers cytokine release, could shed light on how these drugs help to alleviate excessive cytokine production. We also measured the antioxidant activities of dexamethasone and colchicine when scavenging the superoxide radical using cyclic voltammetry methods. The experimental findings are associated with caspase-1 active site affinity towards these compounds. In evaluating our computational and experimental results, we here formulate a mechanism for caspase-1 inhibition by these drugs, which involves the active site amino acid Cys285 residue and is mediated by a transfer of protons, involving His237 and Ser339. It is proposed that the molecular moiety targeted by all of these drugs is a carbonyl group which establishes a S(Cys285)–C(carbonyl) covalent bond. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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16 pages, 3605 KiB

Open AccessArticle

Exploring the Catalytic Mechanism of the RNA Cap Modification by nsp16-nsp10 Complex of SARS-CoV-2 through a QM/MM Approach

by José Rogério A. Silva, Jaime Urban, Edson Araújo, Jerônimo Lameira, Vicent Moliner and Cláudio Nahum Alves

Int. J. Mol. Sci. 2022, 23(1), 300; https://doi.org/10.3390/ijms23010300 - 28 Dec 2021

Cited by 4 | Viewed by 2862

Abstract

The inhibition of key enzymes that may contain the viral replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have assumed central importance in drug discovery projects. Nonstructural proteins (nsps) are essential for RNA capping and coronavirus replication since it protects the virus [...] Read more.

The inhibition of key enzymes that may contain the viral replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have assumed central importance in drug discovery projects. Nonstructural proteins (nsps) are essential for RNA capping and coronavirus replication since it protects the virus from host innate immune restriction. In particular, nonstructural protein 16 (nsp16) in complex with nsp10 is a Cap-0 binding enzyme. The heterodimer formed by nsp16-nsp10 methylates the 5′-end of virally encoded mRNAs to mimic cellular mRNAs and thus it is one of the enzymes that is a potential target for antiviral therapy. In this study, we have evaluated the mechanism of the 2′-O methylation of the viral mRNA cap using hybrid quantum mechanics/molecular mechanics (QM/MM) approach. It was found that the calculated free energy barriers obtained at M062X/6-31+G(d,p) is in agreement with experimental observations. Overall, we provide a detailed molecular analysis of the catalytic mechanism involving the 2′-O methylation of the viral mRNA cap and, as expected, the results demonstrate that the TS stabilization is critical for the catalysis. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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17 pages, 2184 KiB

Open AccessArticle

Iota-Carrageenan Inhibits Replication of SARS-CoV-2 and the Respective Variants of Concern Alpha, Beta, Gamma and Delta

by Maria Fröba, Maximilian Große, Christian Setz, Pia Rauch, Janina Auth, Lucas Spanaus, Jan Münch, Natalia Ruetalo, Michael Schindler, Martina Morokutti-Kurz, Philipp Graf, Eva Prieschl-Grassauer, Andreas Grassauer and Ulrich Schubert

Int. J. Mol. Sci. 2021, 22(24), 13202; https://doi.org/10.3390/ijms222413202 - 08 Dec 2021

Cited by 19 | Viewed by 11063

Abstract

The COVID-19 pandemic continues to spread around the world and remains a major public health threat. Vaccine inefficiency, vaccination breakthroughs and lack of supply, especially in developing countries, as well as the fact that a non-negligible part of the population either refuse vaccination [...] Read more.

The COVID-19 pandemic continues to spread around the world and remains a major public health threat. Vaccine inefficiency, vaccination breakthroughs and lack of supply, especially in developing countries, as well as the fact that a non-negligible part of the population either refuse vaccination or cannot be vaccinated due to age, pre-existing illness or non-response to existing vaccines intensify this issue. This might also contribute to the emergence of new variants, being more efficiently transmitted, more virulent and more capable of escaping naturally acquired and vaccine-induced immunity. Hence, the need of effective and viable prevention options to reduce viral transmission is of outmost importance. In this study, we investigated the antiviral effect of iota-, lambda- and kappa-carrageenan, sulfated polysaccharides extracted from red seaweed, on SARS-CoV-2 Wuhan type and the spreading variants of concern (VOCs) Alpha, Beta, Gamma and Delta. Carrageenans as part of broadly used nasal and mouth sprays as well as lozenges have the potential of first line defense to inhibit the infection and transmission of SARS-CoV-2. Here, we demonstrate by using a SARS-CoV-2 spike pseudotyped lentivirus particles (SSPL) system and patient-isolated SARS-CoV-2 VOCs to infect transgenic A549ACE2/TMPRSS2 and Calu-3 human lung cells that all three carrageenan types exert antiviral activity. Iota-carrageenan exhibits antiviral activity with comparable IC₅₀ values against the SARS-CoV-2 Wuhan type and the VOCs. Altogether, these results indicate that iota-carrageenan might be effective for prophylaxis and treatment of SARS-CoV-2 infections independent of the present and potentially future variants. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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17 pages, 2122 KiB

Open AccessArticle

Lectin from Triticum vulgaris (WGA) Inhibits Infection with SARS-CoV-2 and Its Variants of Concern Alpha and Beta

by Janina Auth, Maria Fröba, Maximilian Große, Pia Rauch, Natalia Ruetalo, Michael Schindler, Martina Morokutti-Kurz, Philipp Graf, Andrea Dolischka, Eva Prieschl-Grassauer, Christian Setz and Ulrich Schubert

Int. J. Mol. Sci. 2021, 22(19), 10205; https://doi.org/10.3390/ijms221910205 - 22 Sep 2021

Cited by 18 | Viewed by 4071

Abstract

Even in the face of global vaccination campaigns, there is still an urgent need for effective antivirals against SARS-CoV-2 and its rapidly spreading variants. Several natural compounds show potential as antiviral substances and have the advantages of broad availabilities and large therapeutic windows. [...] Read more.

Even in the face of global vaccination campaigns, there is still an urgent need for effective antivirals against SARS-CoV-2 and its rapidly spreading variants. Several natural compounds show potential as antiviral substances and have the advantages of broad availabilities and large therapeutic windows. Here, we report that lectin from Triticum vulgaris (Wheat Germ Agglutinin) displays antiviral activity against SARS-CoV-2 and its major Variants of Concern (VoC), Alpha and Beta. In Vero B4 cells, WGA potently inhibits SARS-CoV-2 infection with an IC₅₀ of <10 ng/mL. WGA is effective upon preincubation with the virus or when added during infection. Pull-down assays demonstrate direct binding of WGA to SARS-CoV-2, further strengthening the hypothesis that inhibition of viral entry by neutralizing free virions might be the mode of action behind its antiviral effect. Furthermore, WGA exhibits antiviral activity against human coronavirus OC43, but not against other non-coronaviruses causing respiratory tract infections. Finally, WGA inhibits infection of the lung cell line Calu-3 with wild type and VoC viruses with comparable IC₅₀ values. Altogether, our data indicate that topical administration of WGA might be effective for prophylaxis or treatment of SARS-CoV-2 infections. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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11 pages, 2657 KiB

Open AccessArticle

Virtual Alanine Scan of the Main Protease Active Site in Severe Acute Respiratory Syndrome Coronavirus 2

by Tomoki Nakayoshi, Koichi Kato, Eiji Kurimoto and Akifumi Oda

Int. J. Mol. Sci. 2021, 22(18), 9837; https://doi.org/10.3390/ijms22189837 - 11 Sep 2021

Cited by 2 | Viewed by 1969

Abstract

Recently, inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) have been proposed as potential therapeutic agents for COVID-19. Studying effects of amino acid mutations in the conformation of drug targets is necessary for anticipating drug resistance. In this [...] Read more.

Recently, inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) have been proposed as potential therapeutic agents for COVID-19. Studying effects of amino acid mutations in the conformation of drug targets is necessary for anticipating drug resistance. In this study, with the structure of the SARS-CoV-2 Mpro complexed with a non-covalent inhibitor, we performed molecular dynamics (MD) simulations to determine the conformation of the complex when single amino acid residue in the active site is mutated. As a model of amino acid mutation, we constructed mutant proteins with one residue in the active site mutated to alanine. This method is called virtual alanine scan. The results of the MD simulations showed that the conformation and configuration of the ligand was changed for mutants H163A and E166A, although the structure of the whole protein and of the catalytic dyad did not change significantly, suggesting that mutations in His163 and Glu166 may be linked to drug resistance. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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10 pages, 1872 KiB

Open AccessCommunication

Geraniin Inhibits the Entry of SARS-CoV-2 by Blocking the Interaction between Spike Protein RBD and Human ACE2 Receptor

by Young Soo Kim, Hwan-Suck Chung, Sang Gyun Noh, Bonggi Lee, Hae Young Chung and Jang-Gi Choi

Int. J. Mol. Sci. 2021, 22(16), 8604; https://doi.org/10.3390/ijms22168604 - 10 Aug 2021

Cited by 16 | Viewed by 3420

Abstract

The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the development of vaccines, the emergence of SARS-CoV-2 variants and the absence of effective therapeutics demand the continual investigation of COVID-19. Natural products containing active ingredients [...] Read more.

The coronavirus disease 2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Despite the development of vaccines, the emergence of SARS-CoV-2 variants and the absence of effective therapeutics demand the continual investigation of COVID-19. Natural products containing active ingredients may be good therapeutic candidates. Here, we investigated the effectiveness of geraniin, the main ingredient in medical plants Elaeocarpus sylvestris var. ellipticus and Nephelium lappaceum, for treating COVID-19. The SARS-CoV-2 spike protein binds to the human angiotensin-converting enzyme 2 (hACE2) receptor to initiate virus entry into cells; viral entry may be an important target of COVID-19 therapeutics. Geraniin was found to effectively block the binding between the SARS-CoV-2 spike protein and hACE2 receptor in competitive enzyme-linked immunosorbent assay, suggesting that geraniin might inhibit the entry of SARS-CoV-2 into human epithelial cells. Geraniin also demonstrated a high affinity to both proteins despite a relatively lower equilibrium dissociation constant (K_D) for the spike protein (0.63 μM) than hACE2 receptor (1.12 μM), according to biolayer interferometry-based analysis. In silico analysis indicated geraniin’s interaction with the residues functionally important in the binding between the two proteins. Thus, geraniin is a promising therapeutic agent for COVID-19 by blocking SARS-CoV-2’s entry into human cells. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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15 pages, 3182 KiB

Open AccessArticle

Does the SARS-CoV-2 Spike Protein Receptor Binding Domain Interact Effectively with the DPP4 (CD26) Receptor? A Molecular Docking Study

by Kirsten Cameron, Lina Rozano, Marco Falasca and Ricardo L. Mancera

Int. J. Mol. Sci. 2021, 22(13), 7001; https://doi.org/10.3390/ijms22137001 - 29 Jun 2021

Cited by 22 | Viewed by 3786

Abstract

ACE2 has been established as the main receptor for SARS-CoV-2. Since other human coronaviruses are known to use co-receptors for viral cell entry, it has been suggested that DPP4 (CD26) could be a potential additional binding target or co-receptor, supported by early molecular [...] Read more.

ACE2 has been established as the main receptor for SARS-CoV-2. Since other human coronaviruses are known to use co-receptors for viral cell entry, it has been suggested that DPP4 (CD26) could be a potential additional binding target or co-receptor, supported by early molecular docking simulation studies. However, recent biophysical studies have shown this interaction to be very weak. We have conducted detailed molecular docking simulations to predict the potential binding interactions between the receptor binding domain (RBD) of the spike protein of SARS-CoV-2 and DPP4 and compare them with the interactions observed in the experimentally determined structure of the complex of MERS-CoV with DPP4. Whilst the overall binding mode of the RBD of SARS-CoV-2 to DPP4 is predicted to be similar to that observed in the MERS-CoV-DPP4 complex, including a number of equivalent interactions, important differences in the amino acid sequences of SARS-CoV-2 and MERS-CoV result in substantially weakened interactions with DPP4. This is shown to arise from differences in the predicted proximity, nature and secondary structure at the binding interface on the RBD of SARS-CoV-2. These findings do not support DPP4 being a significant receptor for SARS-CoV-2. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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12 pages, 830 KiB

Open AccessArticle

Influence of Previous COVID-19 and Mastitis Infections on the Secretion of Brain-Derived Neurotrophic Factor and Nerve Growth Factor in Human Milk

by Veronique Demers-Mathieu, Dustin J. Hines, Rochelle M. Hines, Sirima Lavangnananda, Shawn Fels and Elena Medo

Int. J. Mol. Sci. 2021, 22(8), 3846; https://doi.org/10.3390/ijms22083846 - 08 Apr 2021

Cited by 3 | Viewed by 3165

Abstract

Background: Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) play a critical role in neurodevelopment, where breast milk is a significant dietary source. The impact of previous COVID-19 infection and mastitis on the concentration of BDNF and NGF in human milk was [...] Read more.

Background: Brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) play a critical role in neurodevelopment, where breast milk is a significant dietary source. The impact of previous COVID-19 infection and mastitis on the concentration of BDNF and NGF in human milk was investigated. Methods: Concentrations of BDNF and NGF were measured via ELISA in human milk samples collected from 12 mothers with a confirmed COVID-19 PCR, 13 mothers with viral symptoms suggestive of COVID-19, and 22 unexposed mothers (pre-pandemic Ctl-2018). These neurotrophins were also determined in 12 mothers with previous mastitis and 18 mothers without mastitis. Results: The NGF concentration in human milk was lower in the COVID-19 PCR and viral symptoms groups than in the unexposed group, but BDNF did not differ significantly. Within the COVID-19 group, BDNF was higher in mothers who reported headaches or loss of smell/taste when compared with mothers without the respective symptom. BDNF was lower in mothers with mastitis than in mothers without mastitis. Conclusions: Previous COVID-19 and mastitis infections changed differently the secretion of NGF and BDNF in human milk. Whether the changes in NGF and BDNF levels in milk from mothers with infection influence their infant’s development remains to be investigated. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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Review

Jump to: Editorial, Research

25 pages, 23589 KiB

Open AccessReview

A Deadly Embrace: Hemagglutination Mediated by SARS-CoV-2 Spike Protein at Its 22 N-Glycosylation Sites, Red Blood Cell Surface Sialoglycoproteins, and Antibody

by David E. Scheim

Int. J. Mol. Sci. 2022, 23(5), 2558; https://doi.org/10.3390/ijms23052558 - 25 Feb 2022

Cited by 13 | Viewed by 8445

Abstract

Rouleaux (stacked clumps) of red blood cells (RBCs) observed in the blood of COVID-19 patients in three studies call attention to the properties of several enveloped virus strains dating back to seminal findings of the 1940s. For COVID-19, key such properties are: (1) [...] Read more.

Rouleaux (stacked clumps) of red blood cells (RBCs) observed in the blood of COVID-19 patients in three studies call attention to the properties of several enveloped virus strains dating back to seminal findings of the 1940s. For COVID-19, key such properties are: (1) SARS-CoV-2 binds to RBCs in vitro and also in the blood of COVID-19 patients; (2) although ACE2 is its target for viral fusion and replication, SARS-CoV-2 initially attaches to sialic acid (SA) terminal moieties on host cell membranes via glycans on its spike protein; (3) certain enveloped viruses express hemagglutinin esterase (HE), an enzyme that releases these glycan-mediated bindings to host cells, which is expressed among betacoronaviruses in the common cold strains but not the virulent strains, SARS-CoV, SARS-CoV-2 and MERS. The arrangement and chemical composition of the glycans at the 22 N-glycosylation sites of SARS-CoV-2 spike protein and those at the sialoglycoprotein coating of RBCs allow exploration of specifics as to how virally induced RBC clumping may form. The in vitro and clinical testing of these possibilities can be sharpened by the incorporation of an existing anti-COVID-19 therapeutic that has been found in silico to competitively bind to multiple glycans on SARS-CoV-2 spike protein. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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18 pages, 2727 KiB

Open AccessReview

A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

by Guillem Macip, Pol Garcia-Segura, Júlia Mestres-Truyol, Bryan Saldivar-Espinoza, Gerard Pujadas and Santiago Garcia-Vallvé

Int. J. Mol. Sci. 2022, 23(1), 259; https://doi.org/10.3390/ijms23010259 - 27 Dec 2021

Cited by 29 | Viewed by 5801

Abstract

In this review, we collected 1765 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M-pro inhibitors from the bibliography and other sources, such as the COVID Moonshot project and the ChEMBL database. This set of inhibitors includes only those compounds whose inhibitory capacity, mainly [...] Read more.

In this review, we collected 1765 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) M-pro inhibitors from the bibliography and other sources, such as the COVID Moonshot project and the ChEMBL database. This set of inhibitors includes only those compounds whose inhibitory capacity, mainly expressed as the half-maximal inhibitory concentration (IC₅₀) value, against M-pro from SARS-CoV-2 has been determined. Several covalent warheads are used to treat covalent and non-covalent inhibitors separately. Chemical space, the variation of the IC₅₀ inhibitory activity when measured by different methods or laboratories, and the influence of 1,4-dithiothreitol (DTT) are discussed. When available, we have collected the values of inhibition of viral replication measured with a cellular antiviral assay and expressed as half maximal effective concentration (EC₅₀) values, and their possible relationship to inhibitory potency against M-pro is analyzed. Finally, the most potent covalent and non-covalent inhibitors that simultaneously inhibit the SARS-CoV-2 M-pro and the virus replication in vitro are discussed. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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28 pages, 20522 KiB

Open AccessReview

Natural Bioactive Molecules: An Alternative Approach to the Treatment and Control of COVID-19

by Fahadul Islam, Shabana Bibi, Atkia Farzana Khan Meem, Md. Mohaimenul Islam, Md. Saidur Rahaman, Sristy Bepary, Md. Mizanur Rahman, Md. Mominur Rahman, Amin Elzaki, Samih Kajoak, Hamid Osman, Mohamed ElSamani, Mayeen Uddin Khandaker, Abubakr M. Idris and Talha Bin Emran

Int. J. Mol. Sci. 2021, 22(23), 12638; https://doi.org/10.3390/ijms222312638 - 23 Nov 2021

Cited by 42 | Viewed by 5335

Abstract

Several coronaviruses (CoVs) have been associated with serious health hazards in recent decades, resulting in the deaths of thousands around the globe. The recent coronavirus pandemic has emphasized the importance of discovering novel and effective antiviral medicines as quickly as possible to prevent [...] Read more.

Several coronaviruses (CoVs) have been associated with serious health hazards in recent decades, resulting in the deaths of thousands around the globe. The recent coronavirus pandemic has emphasized the importance of discovering novel and effective antiviral medicines as quickly as possible to prevent more loss of human lives. Positive-sense RNA viruses with group spikes protruding from their surfaces and an abnormally large RNA genome enclose CoVs. CoVs have already been related to a range of respiratory infectious diseases possibly fatal to humans, such as MERS, SARS, and the current COVID-19 outbreak. As a result, effective prevention, treatment, and medications against human coronavirus (HCoV) is urgently needed. In recent years, many natural substances have been discovered with a variety of biological significance, including antiviral properties. Throughout this work, we reviewed a wide range of natural substances that interrupt the life cycles for MERS and SARS, as well as their potential application in the treatment of COVID-19. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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29 pages, 2575 KiB

Open AccessReview

Molecular Mechanisms of Possible Action of Phenolic Compounds in COVID-19 Protection and Prevention

by Nikola Gligorijevic, Mirjana Radomirovic, Olgica Nedic, Marija Stojadinovic, Urmila Khulal, Dragana Stanic-Vucinic and Tanja Cirkovic Velickovic

Int. J. Mol. Sci. 2021, 22(22), 12385; https://doi.org/10.3390/ijms222212385 - 17 Nov 2021

Cited by 13 | Viewed by 3861

Abstract

The worldwide outbreak of COVID-19 was caused by a pathogenic virus called Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Therapies against SARS-CoV-2 target the virus or human cells or the immune system. However, therapies based on specific antibodies, such as vaccines and monoclonal antibodies, [...] Read more.

The worldwide outbreak of COVID-19 was caused by a pathogenic virus called Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). Therapies against SARS-CoV-2 target the virus or human cells or the immune system. However, therapies based on specific antibodies, such as vaccines and monoclonal antibodies, may become inefficient enough when the virus changes its antigenicity due to mutations. Polyphenols are the major class of bioactive compounds in nature, exerting diverse health effects based on their direct antioxidant activity and their effects in the modulation of intracellular signaling. There are currently numerous clinical trials investigating the effects of polyphenols in prophylaxis and the treatment of COVID-19, from symptomatic, via moderate and severe COVID-19 treatment, to anti-fibrotic treatment in discharged COVID-19 patients. Antiviral activities of polyphenols and their impact on immune system modulation could serve as a solid basis for developing polyphenol-based natural approaches for preventing and treating COVID-19. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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23 pages, 2174 KiB

Open AccessReview

Putative Role of Vitamin D for COVID-19 Vaccination

by Sheng-Kang Chiu, Kuo-Wang Tsai, Chia-Chao Wu, Cai-Mei Zheng, Chung-Hsiang Yang, Wan-Chung Hu, Yi-Chou Hou, Kuo-Cheng Lu and You-Chen Chao

Int. J. Mol. Sci. 2021, 22(16), 8988; https://doi.org/10.3390/ijms22168988 - 20 Aug 2021

Cited by 32 | Viewed by 10763

Abstract

Severe acute respiratory syndrome coronavirus 2 is a new, highly pathogenic virus that has recently elicited a global pandemic called the 2019 coronavirus disease (COVID-19). COVID-19 is characterized by significant immune dysfunction, which is caused by strong but unregulated innate immunity with depressed [...] Read more.

Severe acute respiratory syndrome coronavirus 2 is a new, highly pathogenic virus that has recently elicited a global pandemic called the 2019 coronavirus disease (COVID-19). COVID-19 is characterized by significant immune dysfunction, which is caused by strong but unregulated innate immunity with depressed adaptive immunity. Reduced and delayed responses to interferons (IFN-I/IFN-III) can increase the synthesis of proinflammatory cytokines and extensive immune cell infiltration into the airways, leading to pulmonary disease. The development of effective treatments for severe COVID-19 patients relies on our knowledge of the pathophysiological components of this imbalanced innate immune response. Strategies to address innate response factors will be essential. Significant efforts are currently underway to develop vaccines against SARS-CoV-2. COVID-19 vaccines, such as inactivated DNA, mRNA, and protein subunit vaccines, have already been applied in clinical use. Various vaccines display different levels of effectiveness, and it is important to continue to optimize and update their composition in order to increase their effectiveness. However, due to the continuous emergence of variant viruses, improving the immunity of the general public may also increase the effectiveness of the vaccines. Many observational studies have demonstrated that serum levels of vitamin D are inversely correlated with the incidence or severity of COVID-19. Extensive evidence has shown that vitamin D supplementation could be vital in mitigating the progression of COVID-19 to reduce its severity. Vitamin D defends against SARS-CoV-2 through a complex mechanism through interactions between the modulation of innate and adaptive immune reactions, ACE2 expression, and inhibition of the renin-angiotensin system (RAS). However, it remains unclear whether Vit-D also plays an important role in the effectiveness of different COVID-19 vaccines. Based on analysis of the molecular mechanism involved, we speculated that vit-D, via various immune signaling pathways, plays a complementary role in the development of vaccine efficacy. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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18 pages, 2253 KiB

Open AccessReview

Do Changes in ACE-2 Expression Affect SARS-CoV-2 Virulence and Related Complications: A Closer Look into Membrane-Bound and Soluble Forms

by Huseyin C. Yalcin, Vijayakumar Sukumaran, Mahmoud Khatib A. A. Al-Ruweidi and Samar Shurbaji

Int. J. Mol. Sci. 2021, 22(13), 6703; https://doi.org/10.3390/ijms22136703 - 23 Jun 2021

Cited by 27 | Viewed by 8200

Abstract

The SARS-CoV-2 virus utilizes angiotensin converting enzyme (ACE-2) for cell entry and infection. This enzyme has important functions in the renin-angiotensin aldosterone system to preserve cardiovascular function. In addition to the heart, it is expressed in many tissues including the lung, [...] Read more.

The SARS-CoV-2 virus utilizes angiotensin converting enzyme (ACE-2) for cell entry and infection. This enzyme has important functions in the renin-angiotensin aldosterone system to preserve cardiovascular function. In addition to the heart, it is expressed in many tissues including the lung, intestines, brain, and kidney, however, its functions in these organs are mostly unknown. ACE-2 has membrane-bound and soluble forms. Its expression levels are altered in disease states and by a variety of medications. Currently, it is not clear how altered ACE-2 levels influence ACE-2 virulence and relevant complications. In addition, membrane-bound and soluble forms are thought to have different effects. Most work on this topic in the literature is on the SARS-CoV virus that has a high genetic resemblance to SARS-Co-V-2 and also uses ACE-2 enzyme to enter the cell, but with much lower affinity. More recent studies on SARS-CoV-2 are mainly clinical studies aiming at relating the effect of medications that are thought to influence ACE-2 levels, with COVID-19 outcomes for patients under these medications. This review paper aims to summarize what is known about the relationship between ACE-2 levels and SARS-CoV/SARS-CoV-2 virulence under altered ACE-2 expression states. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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18 pages, 3823 KiB

Open AccessReview

Estrogen Receptor Modulators in Viral Infections Such as SARS−CoV−2: Therapeutic Consequences

by Nikita Abramenko, Fréderic Vellieux, Petra Tesařová, Zdeněk Kejík, Robert Kaplánek, Lukáš Lacina, Barbora Dvořánková, Daniel Rösel, Jan Brábek, Adam Tesař, Milan Jakubek and Karel Smetana, Jr.

Int. J. Mol. Sci. 2021, 22(12), 6551; https://doi.org/10.3390/ijms22126551 - 18 Jun 2021

Cited by 15 | Viewed by 3980

Abstract

COVID-19 is a pandemic respiratory disease caused by the SARS−CoV−2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient’s death. [...] Read more.

COVID-19 is a pandemic respiratory disease caused by the SARS−CoV−2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient’s death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient’s organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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14 pages, 1418 KiB

Open AccessReview

Effects of SARS-CoV-2 on Cardiovascular System: The Dual Role of Angiotensin-Converting Enzyme 2 (ACE2) as the Virus Receptor and Homeostasis Regulator-Review

by Aneta Aleksova, Giulia Gagno, Gianfranco Sinagra, Antonio Paolo Beltrami, Milijana Janjusevic, Giuseppe Ippolito, Alimuddin Zumla, Alessandra Lucia Fluca and Federico Ferro

Int. J. Mol. Sci. 2021, 22(9), 4526; https://doi.org/10.3390/ijms22094526 - 26 Apr 2021

Cited by 48 | Viewed by 5963

Abstract

Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of Coronavirus Disease-2019 (COVID-19) in humans. ACE-2 is a type I transmembrane metallocarboxypeptidase expressed in vascular endothelial cells, alveolar type 2 lung epithelial cells, renal tubular [...] Read more.

Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of Coronavirus Disease-2019 (COVID-19) in humans. ACE-2 is a type I transmembrane metallocarboxypeptidase expressed in vascular endothelial cells, alveolar type 2 lung epithelial cells, renal tubular epithelium, Leydig cells in testes and gastrointestinal tract. ACE2 mediates the interaction between host cells and SARS-CoV-2 spike (S) protein. However, ACE2 is not only a SARS-CoV-2 receptor, but it has also an important homeostatic function regulating renin-angiotensin system (RAS), which is pivotal for both the cardiovascular and immune systems. Therefore, ACE2 is the key link between SARS-CoV-2 infection, cardiovascular diseases (CVDs) and immune response. Susceptibility to SARS-CoV-2 seems to be tightly associated with ACE2 availability, which in turn is determined by genetics, age, gender and comorbidities. Severe COVID-19 is due to an uncontrolled and excessive immune response, which leads to acute respiratory distress syndrome (ARDS) and multi-organ failure. In spite of a lower ACE2 expression on cells surface, patients with CVDs have a higher COVID-19 mortality rate, which is likely driven by the imbalance between ADAM metallopeptidase domain 17 (ADAM17) protein (which is required for cleavage of ACE-2 ectodomain resulting in increased ACE2 shedding), and TMPRSS2 (which is required for spike glycoprotein priming). To date, ACE inhibitors and Angiotensin II Receptor Blockers (ARBs) treatment interruption in patients with chronic comorbidities appears unjustified. The rollout of COVID-19 vaccines provides opportunities to study the effects of different COVID-19 vaccines on ACE2 in patients on treatment with ACEi/ARB. Full article

(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)

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