Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2

Gaynor, Katherine U.; Vaysburd, Marina; Harman, Maximilian A. J.; Albecka, Anna; Jeffrey, Philip D.; Beswick, Paul J.; Papa, Guido; Chen, Liuhong; Mallery, Donna L.; McGuinness, Brian; Rietschoten, Katerine Van; Stanway, Steven J.; Brear, P.; Lulla, Aleksei; Ciazynska, Katarzyna A.; Chang, Veronica T.; Sharp, Joanne; Neary, Megan; Box, Helen; Herriott, Jo; Kijak, Edyta; Tatham, Lee; Bentley, Eleanor G.; Sharma, Parul; Kirby, Adam; Han, Xiao; Stewart, James P.; Owen, Andrew; Briggs, John; Hyvönen, Marko; Skynner, Michael J.; James, Leo C.

doi:10.1038/s41467-023-39158-1

Cited by 9 publications

(6 citation statements)

References 60 publications

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“…To investigate this, the genomic variation of SARS-CoV-2 was evaluated in an immune compromised host, in the absence and presence of medical countermeasures. We have developed animal models of COVID-19 to be able to assess pathogenicity of new variants and develop interventions [25][26][27] . An immune suppressed K18-hACE2 transgenic mouse model was used to simulate patients with severe COVID-19 28,29 .…”

Section: Introductionmentioning

confidence: 99%

The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in severe models of COVID-19

Penrice-Randal,

Bentley,

Sharma

et al. 2024

Preprint

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Objectives: Immunocompromised individuals are susceptible to severe COVID-19 and potentially contribute to the emergence of variants with altered pathogenicity due to persistent infection. This study investigated the impact of immunosuppression on SARS-CoV-2 infection in k18-hACE2 mice and the effectiveness of antiviral treatments in this context. Methods: Mice were immunosuppressed using cyclophosphamide and infected with a B lineage of SARS-CoV-2. Molnupiravir and nirmatrelvir, alone and in combination, were administered and viral load and viral sequence diversity was assessed. Results: Treatment of infected but immune compromised mice with both compounds either singly or in combination resulted in decreased viral loads and pathological changes compared to untreated animals. Treatment also abrogated infection of neuronal tissue. However, no consistent changes in the viral consensus sequence were observed, except for the emergence of the S:H655Y mutation. Molnupiravir, but not nirmatrelvir or immunosuppression alone, increased the transition/transversion (Ts/Tv) ratio, indicative of A>G and C>U mutations. Notably, immunosuppression itself did not appear to promote the emergence of mutations characteristic of variants of concern (VOCs). Conclusions: Further investigations are warranted to fully understand the role of immunocompromised individuals in VOC development and to inform optimised public health strategies. It is more likely that immunodeficiency promotes viral persistence but does not necessarily lead to substantial consensus-level changes in the absence of antiviral selection pressure. Molnupiravir, compared to nirmatrelvir, shows a stronger mutagenic effect in this model.

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Section: Introductionmentioning

confidence: 99%

The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in severe models of COVID-19

Penrice-Randal,

Bentley,

Sharma

et al. 2024

Preprint

Self Cite

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“…Phages play an important role in related studies. Gaynor et al ( 112 ) utilized phage display library screening to discover small-molecule inhibitors. They found a multivalent bicyclic peptide that acts on the S protein of SARS-CoV-2.…”

Section: Phage Displaymentioning

confidence: 99%

Recent advances in the exploration and discovery of SARS-CoV-2 inhibitory peptides from edible animal proteins

Kong,

Wang,

Zhong

et al. 2024

Front. Nutr.

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The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), which causes the coronavirus disease 2019 (COVID-19), is spreading worldwide. Although the COVID-19 epidemic has passed its peak of transmission, the harm it has caused deserves our attention. Scientists are striving to develop medications that can effectively treat COVID-19 symptoms without causing any adverse reactions. SARS-CoV-2 inhibitory peptides derived from animal proteins have a wide range of functional activities in addition to safety. Identifying animal protein sources is crucial to obtaining SARS-CoV-2 inhibitory peptides from animal sources. This review aims to reveal the mechanisms of action of these peptides on SARS-CoV-2 and the possibility of animal proteins as a material source of SARS-CoV-2 inhibitory peptides. Also, it introduces the utilization of computer-aided design methods, phage display, and drug delivery strategies in the research on SARS-CoV-2 inhibitor peptides from animal proteins. In order to identify new antiviral peptides and boost their efficiency, we recommend investigating the interaction between SARS-CoV-2 inhibitory peptides from animal protein sources and non-structural proteins (Nsps) using a variety of technologies, including computer-aided drug approaches, phage display techniques, and drug delivery techniques. This article provides useful information for the development of novel anti-COVID-19 drugs.

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“…However, monotherapy with VIR-576 showed fast clearances and required infusion of high doses of the peptide. , Altogether, HIV-1 entry can be targeted by agents that block CD4 receptor or CXCR4 and CCR5 co-receptor engagement, as well as steps involved in membrane fusion. Combining antiretroviral peptides with different modes of action may enhance their potency, prevent the development of drug resistance, and increase the bioavailability and in vivo half-life due to their enlarged size and combined action. While solid-phase peptide synthesis or native chemical ligation can be used to combine two different peptide sequences, there are limitations.…”

Section: Introductionmentioning

confidence: 99%

Peptide Bispecifics Inhibiting HIV-1 Infection by an Orthogonal Chemical and Supramolecular Strategy

Schauenburg,

Zech,

Heck

et al. 2023

Bioconjugate Chem.

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Viral infections pose a significant threat to human health, and effective antiviral strategies are urgently needed. Antiviral peptides have emerged as a promising class of therapeutic agents due to their unique properties and mechanisms of action. While effective on their own, combining antiviral peptides may allow us to enhance their potency and to prevent viral resistance. Here, we developed an orthogonal chemical strategy to prepare a heterodimeric peptide conjugate assembled on a protein-based nanoplatform. Specifically, we combined the optimized version of two peptides inhibiting HIV-1 by distinct mechanisms. Virus-inhibitory peptide (VIRIP) is a 20 amino acid fragment of α1-antitrypsin that inhibits HIV-1 by targeting the gp41 fusion peptide. Endogenous peptide inhibitor of CXCR4 (EPI-X4) is a 16-residue fragment of human serum albumin that prevents HIV-1 entry by binding to the viral CXCR4 co-receptor. Optimized forms of both peptides are assembled on supramolecular nanoplatforms through the streptavidin− biotin interaction. We show that the construct consisting of the two different peptides (SAv-VIR-102C9-EPI-X4 JM#173-C) shows increased activity against CCR5-and CXCR4-tropic HIV-1 variants. Our results are a proof of concept that peptides with different modes of action can be assembled on nanoplatforms to enhance their antiviral activity.

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Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2

Cited by 9 publications

References 60 publications

The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in severe models of COVID-19

The effect of molnupiravir and nirmatrelvir on SARS-CoV-2 genome diversity in severe models of COVID-19

Recent advances in the exploration and discovery of SARS-CoV-2 inhibitory peptides from edible animal proteins

Peptide Bispecifics Inhibiting HIV-1 Infection by an Orthogonal Chemical and Supramolecular Strategy

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