Editorial

3 pages, 191 KiB

Open AccessEditorial

by William D. Lubell

Biomedicines 2022, 10(8), 2037; https://doi.org/10.3390/biomedicines10082037 - 21 Aug 2022

Cited by 9 | Viewed by 2244

The celebration of one hundred years of insulin therapy in 2021 marked a milestone for the application of peptide-based therapeutics [...] Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

Research

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15 pages, 3498 KiB

Open AccessEditor’s ChoiceArticle

Solubility-Aware Protein Binding Peptide Design Using AlphaFold

by Takatsugu Kosugi and Masahito Ohue

Biomedicines 2022, 10(7), 1626; https://doi.org/10.3390/biomedicines10071626 - 07 Jul 2022

Cited by 7 | Viewed by 4740

Abstract

New protein–protein interactions (PPIs) are identified, but PPIs have different physicochemical properties compared with conventional targets, making it difficult to use small molecules. Peptides offer a new modality to target PPIs, but designing appropriate peptide sequences by computation is challenging. Recently, AlphaFold and [...] Read more.

New protein–protein interactions (PPIs) are identified, but PPIs have different physicochemical properties compared with conventional targets, making it difficult to use small molecules. Peptides offer a new modality to target PPIs, but designing appropriate peptide sequences by computation is challenging. Recently, AlphaFold and RoseTTAFold have made it possible to predict protein structures from amino acid sequences with ultra-high accuracy, enabling de novo protein design. We designed peptides likely to have PPI as the target protein using the “binder hallucination” protocol of AfDesign, a de novo protein design method using AlphaFold. However, the solubility of the peptides tended to be low. Therefore, we designed a solubility loss function using solubility indices for amino acids and developed a solubility-aware AfDesign binder hallucination protocol. The peptide solubility in sequences designed using the new protocol increased with the weight of the solubility loss function; moreover, they captured the characteristics of the solubility indices. Moreover, the new protocol sequences tended to have higher affinity than random or single residue substitution sequences when evaluated by docking binding affinity. Our approach shows that it is possible to design peptide sequences that can bind to the interface of PPI while controlling solubility. Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

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12 pages, 1724 KiB

Open AccessArticle

Enhancing the Bioactivity of Bicyclic Peptides Targeted to Grb7-SH2 by Restoring Cell Permeability

by Natasha P. Sturre, Rhys N. Colson, Neelam Shah, Gabrielle M. Watson, Xue Yang, Matthew C. J. Wilce, John T. Price and Jacqueline A. Wilce

Biomedicines 2022, 10(5), 1145; https://doi.org/10.3390/biomedicines10051145 - 16 May 2022

Cited by 2 | Viewed by 1554

Abstract

The development of peptide inhibitors against intracellular targets depends upon the dual challenge of achieving a high affinity and specificity for the target and maintaining cellular permeability for biological activity. Previous efforts to develop bicyclic peptides targeted to the Grb7 signalling protein implicated [...] Read more.

The development of peptide inhibitors against intracellular targets depends upon the dual challenge of achieving a high affinity and specificity for the target and maintaining cellular permeability for biological activity. Previous efforts to develop bicyclic peptides targeted to the Grb7 signalling protein implicated in HER2+ve cancer progression have resulted in improved affinity. However, these same peptides demonstrated a lowered activity due to their decreased ability to penetrate cell membranes. Here, we report the testing of a new series of bicyclic G7 peptides designed to possess improved bioactivity. We discovered that the incorporation of two amino acids (Phe-Pro, Phe-Trp or Phe-Arg) within the bicyclic peptide framework maintains an enhanced binding affinity for the Grb7-SH2 domain compared to that of the first-generation monocyclic peptide G7-18NATE. Structure determination using X-ray crystallography revealed that the mode of binding by the expanded bicyclic G7 peptide is analogous to that of G7-18NATE. Interestingly, while the bicyclic peptide containing Phe-Trp did not display the highest affinity for Grb7-SH2 in the series, it was the most potent inhibitor of HER2+ve SKBR3 breast cancer cell migration when coupled to Penetratin. Together, this demonstrates that peptide flexibility as well as the amino acid tryptophan can play important roles in the uptake of peptides into the cell. Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

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11 pages, 1207 KiB

Open AccessCommunication

TRPV1 Blocker HCRG21 Suppresses TNF-α Production and Prevents the Development of Edema and Hypersensitivity in Carrageenan-Induced Acute Local Inflammation

by Oksana Sintsova, Irina Gladkikh, Anna Klimovich, Yulia Palikova, Viktor Palikov, Olga Styshova, Margarita Monastyrnaya, Igor Dyachenko, Sergey Kozlov and Elena Leychenko

Biomedicines 2021, 9(7), 716; https://doi.org/10.3390/biomedicines9070716 - 23 Jun 2021

Cited by 6 | Viewed by 2134

Abstract

Currently the TRPV1 (transient receptor potential vanilloid type 1) channel is considered to be one of the main targets for pro-inflammatory mediators including TNF-α. Similarly, the inhibition of TRPV1 activity in the peripheral nervous system affects pro-inflammatory mediator production and enhances analgesia in [...] Read more.

Currently the TRPV1 (transient receptor potential vanilloid type 1) channel is considered to be one of the main targets for pro-inflammatory mediators including TNF-α. Similarly, the inhibition of TRPV1 activity in the peripheral nervous system affects pro-inflammatory mediator production and enhances analgesia in total. In this study, the analgesic and anti-inflammatory effects of HCRG21, the first peptide blocker of TRPV1, were demonstrated in a mice model of carrageenan-induced paw edema. HCRG21 in doses of 0.1 and 1 mg/kg inhibited edema formation compared to the control, demonstrated complete edema disappearance in 24 h in a dose of 1 mg/kg, and effectively reduced the productionof TNF-α in both doses examined. ELISA analysis of blood taken 24 h after carrageenan administration showed a dramatic cytokine value decrease to 25 pg/mL by HCRG21 versus 100 pg/mL in the negative control group, which was less than the TNF-α level in the intact group (40 pg/mL). The HCRG21 demonstrated potent analgesic effects on the models of mechanical and thermal hyperalgesia in carrageenan-induced paw edema. The HCRG21 relief effect was comparable to that of indomethacin taken orally in a dose of 5 mg/kg, but was superior to this nonsteroidal anti-inflammatory drug (NSAID) in duration (which lasted 24 h) in the mechanical sensitivity experiment. The results confirm the existence of a close relationship between TRPV1 activity and TNF-α production once again, and prove the superior pharmacological potential of TRPV1 blockers and the HCRG21 peptide in particular. Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

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17 pages, 3240 KiB

Open AccessArticle

Sea Anemone Kunitz-Type Peptides Demonstrate Neuroprotective Activity in the 6-Hydroxydopamine Induced Neurotoxicity Model

by Oksana Sintsova, Irina Gladkikh, Margarita Monastyrnaya, Valentin Tabakmakher, Ekaterina Yurchenko, Ekaterina Menchinskaya, Evgeny Pislyagin, Yaroslav Andreev, Sergey Kozlov, Steve Peigneur, Jan Tytgat, Dmitry Aminin, Emma Kozlovskaya and Elena Leychenko

Biomedicines 2021, 9(3), 283; https://doi.org/10.3390/biomedicines9030283 - 10 Mar 2021

Cited by 12 | Viewed by 2589

Abstract

Kunitz-type peptides from venomous animals have been known to inhibit different proteinases and also to modulate ion channels and receptors, demonstrating analgesic, anti-inflammatory, anti-histamine and many other biological activities. At present, there is evidence of their neuroprotective effects. We have studied eight Kunitz-type [...] Read more.

Kunitz-type peptides from venomous animals have been known to inhibit different proteinases and also to modulate ion channels and receptors, demonstrating analgesic, anti-inflammatory, anti-histamine and many other biological activities. At present, there is evidence of their neuroprotective effects. We have studied eight Kunitz-type peptides of the sea anemone Heteractis crispa to find molecules with cytoprotective activity in the 6-OHDA-induced neurotoxicity model on neuroblastoma Neuro-2a cells. It has been shown that only five peptides significantly increase the viability of neuronal cells treated with 6-OHDA. The TRPV1 channel blocker, HCRG21, has revealed the neuroprotective effect that could be indirect evidence of TRPV1 involvement in the disorders associated with neurodegeneration. The pre-incubation of Neuro-2a cells with HCRG21 followed by 6-OHDA treatment has resulted in a prominent reduction in ROS production compared the untreated cells. It is possible that the observed effect is due to the ability of the peptide act as an efficient free-radical scavenger. One more leader peptide, InhVJ, has shown a neuroprotective activity and has been studied at concentrations of 0.01–10.0 µM. The target of InhVJ is still unknown, but it was the best of all eight homologous peptides in an absolute cell viability increment on 38% of the control in the 6-OHDA-induced neurotoxicity model. The targets of the other three active peptides remain unknown. Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

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14 pages, 2054 KiB

Open AccessArticle

Pursuing Orally Bioavailable Hepcidin Analogues via Cyclic N-Methylated Mini-Hepcidins

by Daniela Goncalves Monteiro, Johannes W. A. van Dijk, Randy Aliyanto, Eileen Fung, Elizabeta Nemeth, Tomas Ganz, Johan Rosengren and Richard J. Clark

Biomedicines 2021, 9(2), 164; https://doi.org/10.3390/biomedicines9020164 - 08 Feb 2021

Cited by 4 | Viewed by 2231

Abstract

The peptide hormone hepcidin is one of the key regulators of iron absorption, plasma iron levels, and tissue iron distribution. Hepcidin functions by binding to and inducing the internalisation and subsequent lysosomal degradation of ferroportin, which reduces both iron absorption in the gut [...] Read more.

The peptide hormone hepcidin is one of the key regulators of iron absorption, plasma iron levels, and tissue iron distribution. Hepcidin functions by binding to and inducing the internalisation and subsequent lysosomal degradation of ferroportin, which reduces both iron absorption in the gut and export of iron from storage to ultimately decrease systemic iron levels. The key interaction motif in hepcidin has been localised to the highly conserved N-terminal region, comprising the first nine amino acid residues, and has led to the development of mini-hepcidin analogs that induce ferroportin internalisation and have improved drug-like properties. In this work, we have investigated the use of head-to-tail cyclisation and N-methylation of mini-hepcidin as a strategy to increase oral bioavailability by reducing proteolytic degradation and enhancing membrane permeability. We found that backbone cyclisation and N-methylation was well-tolerated in the mini-hepcidin analogues, with the macrocylic analogues often surpassing their linear counterparts in potency. Both macrocyclisation and backbone N-methylation were found to improve the stability of the mini-hepcidins, however, there was no effect on membrane-permeabilizing activity. Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

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16 pages, 2082 KiB

Open AccessArticle

Exploring the Use of Helicogenic Amino Acids for Optimising Single Chain Relaxin-3 Peptide Agonists

by Han Siean Lee, Shu Hui Wang, James T. Daniel, Mohammed Akhter Hossain, Richard J. Clark, Ross A. D. Bathgate and K. Johan Rosengren

Biomedicines 2020, 8(10), 415; https://doi.org/10.3390/biomedicines8100415 - 14 Oct 2020

Cited by 2 | Viewed by 2607

Abstract

Relaxin-3 is a highly conserved two-chain neuropeptide that acts through its endogenous receptor the Relaxin Family Peptide-3 (RXFP3) receptor. The ligand/receptor system is known to modulate several physiological processes, with changes in food intake and anxiety-levels the most well studied in rodent models. [...] Read more.

Relaxin-3 is a highly conserved two-chain neuropeptide that acts through its endogenous receptor the Relaxin Family Peptide-3 (RXFP3) receptor. The ligand/receptor system is known to modulate several physiological processes, with changes in food intake and anxiety-levels the most well studied in rodent models. Agonist and antagonist analogues based on the native two-chain peptide are costly to synthesise and not ideal drug leads. Since RXFP3 interacting residues are found in the relaxin B-chain only, this has been the focus of analogue development. The B-chain is unstructured without the A-chain support, but in single-chain variants structure can be induced by dicarba-based helical stapling strategies. Here we investigated whether alternative helical inducing strategies also can enhance structure and activity at RXFP3. Combinations of the helix inducing α-aminoisobutyric acid (Aib) were incorporated into the sequence of the relaxin-3 B-chain. Aib residues at positions 13, 17 and 18 partially reintroduce helicity and activity of the relaxin-3 B-chain, but other positions are generally not suited for modifications. We identify Thr21 as a putative new receptor contact residue important for RXFP3 binding. Cysteine residues were also incorporated into the sequence and cross-linked with dichloroacetone or α, α’-dibromo-m-xylene. However, in contrast to previously reported dicarba variants, neither were found to promote structure and RXFP3 activity. Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

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15 pages, 2400 KiB

Open AccessArticle

Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na_V Channel Inhibitor

by Kirsten L. McMahon, Hue N.T. Tran, Jennifer R. Deuis, Richard J. Lewis, Irina Vetter and Christina I. Schroeder

Biomedicines 2020, 8(10), 391; https://doi.org/10.3390/biomedicines8100391 - 02 Oct 2020

Cited by 15 | Viewed by 3974

Abstract

Voltage-gated sodium (Na_V) channel subtypes, including Na_V1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ-conotoxins are small, potent Na_V channel inhibitors which represent potential drug leads. Of the 22 µ-conotoxins [...] Read more.

Voltage-gated sodium (Na_V) channel subtypes, including Na_V1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ-conotoxins are small, potent Na_V channel inhibitors which represent potential drug leads. Of the 22 µ-conotoxins characterised so far, only a small number, including KIIIA and CnIIIC, have shown inhibition against human Na_V1.7. We have recently identified a novel µ-conotoxin, SxIIIC, from Conus striolatus. Here we present the isolation of native peptide, chemical synthesis, characterisation of human Na_V channel activity by whole-cell patch-clamp electrophysiology and analysis of the NMR solution structure. SxIIIC displays a unique Na_V channel selectivity profile (1.4 > 1.3 > 1.1 ≈ 1.6 ≈ 1.7 > 1.2 >> 1.5 ≈ 1.8) when compared to other µ-conotoxins and represents one of the most potent human Na_V1.7 putative pore blockers (IC₅₀ 152.2 ± 21.8 nM) to date. NMR analysis reveals the structure of SxIIIC includes the characteristic α-helix seen in other µ-conotoxins. Future investigations into structure-activity relationships of SxIIIC are expected to provide insights into residues important for Na_V channel pore blocker selectivity and subsequently important for chronic pain drug development. Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

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Review

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32 pages, 97739 KiB

Open AccessReview

The Biology of Vasopressin

by Samantha Sparapani, Cassandra Millet-Boureima, Joshua Oliver, Kathy Mu, Pegah Hadavi, Tamar Kalostian, Nazifa Ali, Carla Maria Avelar, Marion Bardies, Brenton Barrow, Minky Benedikt, Giuliana Biancardi, Raminder Bindra, Lisa Bui, Zakaria Chihab, Ashley Cossitt, Jeffrey Costa, Tina Daigneault, Jocelyn Dault, Isa Davidson, Jonathan Dias, Emie Dufour, Sabine El-Khoury, Nargess Farhangdoost, Anika Forget, Alexa Fox, Myriam Gebrael, Maria Concetta Gentile, Olivia Geraci, Ansley Gnanapragasam, Elias Gomah, Elie Haber, Claudia Hamel, Thivya Iyanker, Christina Kalantzis, Sara Kamali, Elsa Kassardjian, Hryssi Krissy Kontos, Thi Bich Uyen Le, Daniella LoScerbo, Yan Fang Low, Danielle Mac Rae, Flore Maurer, Sana Mazhar, Alice Nguyen, Kathy Nguyen-Duong, Chelsea Osborne-Laroche, Hwi Wun Park, Emilie Parolin, Kahlila Paul-Cole, Leah Sarah Peer, Margaux Philippon, Charles-Alexandre Plaisir, Jessica Porras Marroquin, Simran Prasad, Rewaparsad Ramsarun, Saad Razzaq, Samantha Rhainds, Damien Robin, Ryan Scartozzi, Davindra Singh, Sajad Soleimani Fard, Maxim Soroko, Nastaran Soroori Motlagh, Kiri Stern, Laila Toro, M. Wyatt Toure, Stephanie Tran-Huynh, Sarah Trépanier-Chicoine, Claudia Waddingham, Aaliyah Jasmine Weekes, Allison Wisniewski and Chiara Gamberi Show full author list Hide full author list

Biomedicines 2021, 9(1), 89; https://doi.org/10.3390/biomedicines9010089 - 18 Jan 2021

Cited by 25 | Viewed by 14679

Abstract

Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin [...] Read more.

Vasopressins are evolutionarily conserved peptide hormones. Mammalian vasopressin functions systemically as an antidiuretic and regulator of blood and cardiac flow essential for adapting to terrestrial environments. Moreover, vasopressin acts centrally as a neurohormone involved in social and parental behavior and stress response. Vasopressin synthesis in several cell types, storage in intracellular vesicles, and release in response to physiological stimuli are highly regulated and mediated by three distinct G protein coupled receptors. Other receptors may bind or cross-bind vasopressin. Vasopressin is regulated spatially and temporally through transcriptional and post-transcriptional mechanisms, sex, tissue, and cell-specific receptor expression. Anomalies of vasopressin signaling have been observed in polycystic kidney disease, chronic heart failure, and neuropsychiatric conditions. Growing knowledge of the central biological roles of vasopressin has enabled pharmacological advances to treat these conditions by targeting defective systemic or central pathways utilizing specific agonists and antagonists. Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

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26 pages, 2767 KiB

Open AccessReview

Up- or Downregulation of Melanin Synthesis Using Amino Acids, Peptides, and Their Analogs

by Yong Chool Boo

Biomedicines 2020, 8(9), 322; https://doi.org/10.3390/biomedicines8090322 - 01 Sep 2020

Cited by 23 | Viewed by 6889

Abstract

Harmonious synthesis and distribution of melanin in the skin contribute to the expression of beauty and the maintenance of health. When skin pigmentary disorders occur because of internal or external factors or, when there is a need to artificially increase or reduce the [...] Read more.

Harmonious synthesis and distribution of melanin in the skin contribute to the expression of beauty and the maintenance of health. When skin pigmentary disorders occur because of internal or external factors or, when there is a need to artificially increase or reduce the pigmentation level of the skin for aesthetic or therapeutic purposes, various pharmacological therapies are applied but the results are not always satisfactory. Studies have been conducted to improve the efficacy and safety of these treatment strategies. In this review, we present the latest studies regarding peptides and related compounds that may be useful in artificially increasing or reducing skin melanin levels. Certain analogs of α-melanocyte stimulating hormone (MSH) and oligopeptides with the sequences derived from the hormone were shown to promote melanin synthesis in cells and in vivo models. Various amino acids, peptides, their analogs, and their hybrid compounds with other chemical moieties were shown to inhibit tyrosinase (TYR) catalytic activity or downregulate TYR gene expression. Certain peptides were shown to inhibit melanosome biogenesis or induce autophagy, leading to decreased pigmentation. In vivo and clinical evidence are available for some compounds, including [Nle⁴-_D-Phe⁷]-α-MSH, glutathione disulfide, and glycinamide hydrochloride. For many other compounds, additional studies are required to verify their efficacy and safety in vivo and in clinical trials. The accumulating information regarding pro- and antimelanogenic activity of peptides and related compounds will lead to the development of novel drugs for the treatment of skin pigmentary disorders. Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

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25 pages, 6428 KiB

Open AccessReview

Synthesis and Biomedical Potential of Azapeptide Modulators of the Cluster of Differentiation 36 Receptor (CD36)

by Caroline Proulx, Jinqiang Zhang, David Sabatino, Sylvain Chemtob, Huy Ong and William D. Lubell

Biomedicines 2020, 8(8), 241; https://doi.org/10.3390/biomedicines8080241 - 23 Jul 2020

Cited by 14 | Viewed by 3792

Abstract

The innovative development of azapeptide analogues of growth hormone releasing peptide-6 (GHRP-6) has produced selective modulators of the cluster of differentiation 36 receptor (CD36). The azapeptide CD36 modulators curb macrophage-driven inflammation and mitigate atherosclerotic and angiogenic pathology. In macrophages activated with Toll-like receptor-2 [...] Read more.

The innovative development of azapeptide analogues of growth hormone releasing peptide-6 (GHRP-6) has produced selective modulators of the cluster of differentiation 36 receptor (CD36). The azapeptide CD36 modulators curb macrophage-driven inflammation and mitigate atherosclerotic and angiogenic pathology. In macrophages activated with Toll-like receptor-2 heterodimer agonist, they reduced nitric oxide production and proinflammatory cytokine release. In a mouse choroidal explant microvascular sprouting model, they inhibited neovascularization. In murine models of cardiovascular injury, CD36-selective azapeptide modulators exhibited cardioprotective and anti-atherosclerotic effects. In subretinal inflammation models, they altered activated mononuclear phagocyte metabolism and decreased immune responses to alleviate subsequent inflammation-dependent neuronal injury associated with retinitis pigmentosa, diabetic retinopathy and age-related macular degeneration. The translation of GHRP-6 to potent and selective linear and cyclic azapeptide modulators of CD36 is outlined in this review which highlights the relevance of turn geometry for activity and the biomedical potential of prototypes for the beneficial treatment of a wide range of cardiovascular, metabolic and immunological disorders. Full article

(This article belongs to the Special Issue Peptide-Based Drug Development)

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