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Small Molecule Inhibitors of Polymerases Involved in Human Diseases

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 17587

Special Issue Editors

Center for Advanced Biotechnology and Medicine and Department of Chemistry and Chemical Biology, Rutgers University, New Brunswick, NJ, USA
Interests: structural biology; biochemistry; drug discovery; viral protein
Special Issues, Collections and Topics in MDPI journals
Gilead Sciences Inc, 333 Lakeside Drive, Foster City, CA 94404, USA
Interests: Viral DNA and RNA polymerases; antiviral; drug toxicity; mechanism of action

Special Issue Information

Dear Colleagues,

Polymerases are a very diverse superfamily of enzymes that synthesize long chains of nucleic acids. They are essential across all the domains of life and viruses. Therefore, many polymerases are targets of numerous drugs that have often become the first available drugs for treatment of devastating human diseases (nucleosides, as AZT for AIDS treatment, gemcitabine against cancer or, recently, remdesivir against SARS-CoV-2) or game-changers for halting them (non-nucleoside allosteric inhibitors, as exemplified by rilpivirine for AIDS treatment, sofosbuvir against hepatitis C, and rifampicin against tuberculosis). In spite of such successes, compounds targeting polymerases have also experienced high attrition rates in clinical trials due to toxicity and lack of selectivity. Additionally, the current pandemic has put a spotlight on the necessity for broad-range drugs that can help to face the next pandemic, deal with neglected diseases (such as yellow fever or Zika disease) or to address the incoming challenge of antibiotic resistance.

In this context, we are proposing a new Special Issue titled "Small Molecule Inhibitors of Polymerases Involved in Human Diseases". This Special Issue welcomes the submission of original research, communications, and review manuscripts focusing on polymerases as targets for therapy, novel inhibitor and drug discovery strategies, as well as structural and mechanistic characterization of relevant polymerase–inhibitor complexes for human diseases.

Dr. Francesc Xavier Ruiz
Dr. Joy Y. Feng
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • DNA polymerases
  • RNA polymerases
  • antibiotics
  • antiviral
  • anticancer

Published Papers (8 papers)

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Research

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26 pages, 4466 KiB  
Article
Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach
Molecules 2023, 28(7), 3103; https://doi.org/10.3390/molecules28073103 - 30 Mar 2023
Cited by 2 | Viewed by 1709
Abstract
Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host’s immune system leading to acquired immunodeficiency syndrome and potentially death. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Continued [...] Read more.
Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host’s immune system leading to acquired immunodeficiency syndrome and potentially death. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Continued emergence of drug-resistance mutations drives the need for novel drugs that can inhibit HIV-1 replication through new pathways. The viral protein reverse transcriptase (RT) plays a fundamental role in the HIV-1 replication cycle, and multiple approved medications target this enzyme. In this study, fragment-based drug discovery was used to optimize a previously identified hit fragment (compound B-1), which bound RT at a novel site. Three series of compounds were synthesized and evaluated for their HIV-1 RT binding and inhibition. These series were designed to investigate different vectors around the initial hit in an attempt to improve inhibitory activity against RT. Our results show that the 4-position of the core scaffold is important for binding of the fragment to RT, and a lead compound with a cyclopropyl substitution was selected and further investigated. Requirements for binding to the NNRTI-binding pocket (NNIBP) and a novel adjacent site were investigated, with lead compound 27—a minimal but efficient NNRTI—offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Polymerases Involved in Human Diseases)
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15 pages, 8084 KiB  
Article
Identification of Polyphenol Derivatives as Novel SARS-CoV-2 and DENV Non-Nucleoside RdRp Inhibitors
Molecules 2023, 28(1), 160; https://doi.org/10.3390/molecules28010160 - 25 Dec 2022
Cited by 4 | Viewed by 2115
Abstract
The Coronavirus Disease 2019 (COVID-19) and dengue fever (DF) pandemics both remain to be significant public health concerns in the foreseeable future. Anti-SARS-CoV-2 drugs and vaccines are both indispensable to eliminate the epidemic situation. Here, two piperazine-based polyphenol derivatives DF-47 and DF-51 were [...] Read more.
The Coronavirus Disease 2019 (COVID-19) and dengue fever (DF) pandemics both remain to be significant public health concerns in the foreseeable future. Anti-SARS-CoV-2 drugs and vaccines are both indispensable to eliminate the epidemic situation. Here, two piperazine-based polyphenol derivatives DF-47 and DF-51 were identified as potential inhibitors directly blocking the active site of SARS-CoV-2 and DENV RdRp. Data through RdRp inhibition screening of an in-house library and in vitro antiviral study selected DF-47 and DF-51 as effective inhibitors of SARS-CoV-2/DENV polymerase. Moreover, in silico simulation revealed stable binding modes between the DF-47/DF-51 and SARS-CoV-2/DENV RdRp, respectively, including chelating with Mg2+ near polymerase active site. This work discovered the inhibitory effect of two polyphenols on distinct viral RdRp, which are expected to be developed into broad-spectrum, non-nucleoside RdRp inhibitors with new scaffold. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Polymerases Involved in Human Diseases)
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15 pages, 17968 KiB  
Article
The Nucleoside/Nucleotide Analogs Tenofovir and Emtricitabine Are Inactive against SARS-CoV-2
Molecules 2022, 27(13), 4212; https://doi.org/10.3390/molecules27134212 - 30 Jun 2022
Cited by 9 | Viewed by 1947
Abstract
The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase [...] Read more.
The urgent response to the COVID-19 pandemic required accelerated evaluation of many approved drugs as potential antiviral agents against the causative pathogen, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Using cell-based, biochemical, and modeling approaches, we studied the approved HIV-1 nucleoside/tide reverse transcriptase inhibitors (NRTIs) tenofovir (TFV) and emtricitabine (FTC), as well as prodrugs tenofovir alafenamide (TAF) and tenofovir disoproxilfumarate (TDF) for their antiviral effect against SARS-CoV-2. A comprehensive set of in vitro data indicates that TFV, TAF, TDF, and FTC are inactive against SARS-CoV-2. None of the NRTIs showed antiviral activity in SARS-CoV-2 infected A549-hACE2 cells or in primary normal human lung bronchial epithelial (NHBE) cells at concentrations up to 50 µM TAF, TDF, FTC, or 500 µM TFV. These results are corroborated by the low incorporation efficiency of respective NTP analogs by the SARS-CoV-2 RNA-dependent-RNA polymerase (RdRp), and lack of the RdRp inhibition. Structural modeling further demonstrated poor fitting of these NRTI active metabolites at the SARS-CoV-2 RdRp active site. Our data indicate that the HIV-1 NRTIs are unlikely direct-antivirals against SARS-CoV-2, and clinicians and researchers should exercise caution when exploring ideas of using these and other NRTIs to treat or prevent COVID-19. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Polymerases Involved in Human Diseases)
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19 pages, 2158 KiB  
Article
Going Retro, Going Viral: Experiences and Lessons in Drug Discovery from COVID-19
Molecules 2022, 27(12), 3815; https://doi.org/10.3390/molecules27123815 - 14 Jun 2022
Cited by 1 | Viewed by 2163
Abstract
The severity of the COVID-19 pandemic and the pace of its global spread have motivated researchers to opt for repurposing existing drugs against SARS-CoV-2 rather than discover or develop novel ones. For reasons of speed, throughput, and cost-effectiveness, virtual screening campaigns, relying heavily [...] Read more.
The severity of the COVID-19 pandemic and the pace of its global spread have motivated researchers to opt for repurposing existing drugs against SARS-CoV-2 rather than discover or develop novel ones. For reasons of speed, throughput, and cost-effectiveness, virtual screening campaigns, relying heavily on in silico docking, have dominated published reports. A particular focus as a drug target has been the principal active site (i.e., RNA synthesis) of RNA-dependent RNA polymerase (RdRp), despite the existence of a second, and also indispensable, active site in the same enzyme. Here we report the results of our experimental interrogation of several small-molecule inhibitors, including natural products proposed to be effective by in silico studies. Notably, we find that two antibiotics in clinical use, fidaxomicin and rifabutin, inhibit RNA synthesis by SARS-CoV-2 RdRp in vitro and inhibit viral replication in cell culture. However, our mutagenesis studies contradict the binding sites predicted computationally. We discuss the implications of these and other findings for computational studies predicting the binding of ligands to large and flexible protein complexes and therefore for drug discovery or repurposing efforts utilizing such studies. Finally, we suggest several improvements on such efforts ongoing against SARS-CoV-2 and future pathogens as they arise. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Polymerases Involved in Human Diseases)
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17 pages, 1466 KiB  
Article
Synthesis and Anti-Hepatitis B Activities of 3′-Fluoro-2′-Substituted Apionucleosides
Molecules 2022, 27(8), 2413; https://doi.org/10.3390/molecules27082413 - 08 Apr 2022
Viewed by 1418
Abstract
Nucleoside analogues have excellent records as anti-HBV drugs. Chronic infections require long-term administration ultimately leading to drug resistance. Therefore, the search for nucleosides with novel scaffolds is of high importance. Here we report the synthesis of novel 2′-hydroxy- and 2′-hydroxymethyl-apionucleosides, 4 and 5 [...] Read more.
Nucleoside analogues have excellent records as anti-HBV drugs. Chronic infections require long-term administration ultimately leading to drug resistance. Therefore, the search for nucleosides with novel scaffolds is of high importance. Here we report the synthesis of novel 2′-hydroxy- and 2′-hydroxymethyl-apionucleosides, 4 and 5, corresponding triphosphates and phosphoramidate prodrugs. Triphosphate 38 of 2′-hydroxymethyl-apionucleoside 5 exhibited potent inhibition of HBV polymerase with an IC50 value of 120 nM. In an HBV cell-based assay, the phosphoramidate prodrug 39 demonstrated potent activity with an EC50 value of 7.8 nM. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Polymerases Involved in Human Diseases)
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10 pages, 1852 KiB  
Article
A Helquat-like Compound as a Potent Inhibitor of Flaviviral and Coronaviral Polymerases
Molecules 2022, 27(6), 1894; https://doi.org/10.3390/molecules27061894 - 15 Mar 2022
Cited by 3 | Viewed by 2081
Abstract
Positive-sense single-stranded RNA (+RNA) viruses have proven to be important pathogens that are able to threaten and deeply damage modern societies, as illustrated by the ongoing COVID-19 pandemic. Therefore, compounds active against most or many +RNA viruses are urgently needed. Here, we present [...] Read more.
Positive-sense single-stranded RNA (+RNA) viruses have proven to be important pathogens that are able to threaten and deeply damage modern societies, as illustrated by the ongoing COVID-19 pandemic. Therefore, compounds active against most or many +RNA viruses are urgently needed. Here, we present PR673, a helquat-like compound that is able to inhibit the replication of SARS-CoV-2 and tick-borne encephalitis virus in cell culture. Using in vitro polymerase assays, we demonstrate that PR673 inhibits RNA synthesis by viral RNA-dependent RNA polymerases (RdRps). Our results illustrate that the development of broad-spectrum non-nucleoside inhibitors of RdRps is feasible. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Polymerases Involved in Human Diseases)
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Review

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14 pages, 7742 KiB  
Review
Structural and Molecular Basis for Mitochondrial DNA Replication and Transcription in Health and Antiviral Drug Toxicity
Molecules 2023, 28(4), 1796; https://doi.org/10.3390/molecules28041796 - 14 Feb 2023
Cited by 4 | Viewed by 2352
Abstract
Human mitochondrial DNA (mtDNA) is a 16.9 kbp double-stranded, circular DNA, encoding subunits of the oxidative phosphorylation electron transfer chain and essential RNAs for mitochondrial protein translation. The minimal human mtDNA replisome is composed of the DNA helicase Twinkle, DNA polymerase γ, and [...] Read more.
Human mitochondrial DNA (mtDNA) is a 16.9 kbp double-stranded, circular DNA, encoding subunits of the oxidative phosphorylation electron transfer chain and essential RNAs for mitochondrial protein translation. The minimal human mtDNA replisome is composed of the DNA helicase Twinkle, DNA polymerase γ, and mitochondrial single-stranded DNA-binding protein. While the mitochondrial RNA transcription is carried out by mitochondrial RNA polymerase, mitochondrial transcription factors TFAM and TFB2M, and a transcription elongation factor, TEFM, both RNA transcriptions, and DNA replication machineries are intertwined and control mtDNA copy numbers, cellular energy supplies, and cellular metabolism. In this review, we discuss the mechanisms governing these main pathways and the mtDNA diseases that arise from mutations in transcription and replication machineries from a structural point of view. We also address the adverse effect of antiviral drugs mediated by mitochondrial DNA and RNA polymerases as well as possible structural approaches to develop nucleoside reverse transcriptase inhibitor and ribonucleosides analogs with reduced toxicity. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Polymerases Involved in Human Diseases)
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10 pages, 952 KiB  
Review
Opportunities and Challenges in Targeting the Proofreading Activity of SARS-CoV-2 Polymerase Complex
Molecules 2022, 27(9), 2918; https://doi.org/10.3390/molecules27092918 - 03 May 2022
Cited by 4 | Viewed by 2745
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. While the development of vaccines and the emergence of antiviral therapeutics is promising, alternative strategies to combat COVID-19 (and potential future pandemics) remain an unmet need. Coronaviruses feature a [...] Read more.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. While the development of vaccines and the emergence of antiviral therapeutics is promising, alternative strategies to combat COVID-19 (and potential future pandemics) remain an unmet need. Coronaviruses feature a unique mechanism that may present opportunities for therapeutic intervention: the RNA polymerase complex of coronaviruses is distinct in its ability to proofread and remove mismatched nucleotides during genome replication and transcription. The proofreading activity has been linked to the exonuclease (ExoN) activity of non-structural protein 14 (NSP14). Here, we review the role of NSP14, and other NSPs, in SARS-CoV-2 replication and describe the assays that have been developed to assess the ExoN function. We also review the nucleoside analogs and non-nucleoside inhibitors known to interfere with the proofreading activity of NSP14. Although not yet validated, the potential use of non-nucleoside proofreading inhibitors in combination with chain-terminating nucleosides may be a promising avenue for the development of anti-CoV agents. Full article
(This article belongs to the Special Issue Small Molecule Inhibitors of Polymerases Involved in Human Diseases)
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