Stapled peptides as potential inhibitors of SARS‐CoV‐2 binding to the hACE2 receptor

Tzotzos, Susan

doi:10.1002/psc.3409

Cited by 8 publications

(3 citation statements)

References 52 publications

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“…In HIV-1 patients, ENF has demonstrated strong effectiveness, favourable pharmacological characteristics, and safety data. 51 Contrary to this, patients with HIV-2 are intrinsically resistant to ENF.…”

Section: Fusion Inhibitorsmentioning

confidence: 99%

“…By competitively blocking the HR‐2 component of gp41 from attaching to HR‐1, it prevents gp41 from binding to another trimeric heptad domain 50 . In HIV‐1 patients, ENF has demonstrated strong effectiveness, favourable pharmacological characteristics, and safety data 51 . Contrary to this, patients with HIV‐2 are intrinsically resistant to ENF.…”

Section: Current Hiv‐1 Anti‐retrovirals and The Mechanisms Of Actionmentioning

confidence: 99%

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Pharmacological advances in anti‐retroviral therapy for human immunodeficiency virus‐1 infection: A comprehensive review

Azzman,

Gill,

Hassan

et al. 2024

Reviews in Medical Virology

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The discovery of anti‐retroviral (ARV) drugs over the past 36 years has introduced various classes, including nucleoside/nucleotide reverse transcriptase inhibitors, non‐nucleoside reverse transcriptase inhibitors, protease inhibitor, fusion, and integrase strand transfer inhibitors inhibitors. The introduction of combined highly active anti‐retroviral therapies in 1996 was later proven to combat further ARV drug resistance along with enhancing human immunodeficiency virus (HIV) suppression. As though the development of ARV therapies was continuously expanding, the variation of action caused by ARV drugs, along with its current updates, was not comprehensively discussed, particularly for HIV‐1 infection. Thus, a range of HIV‐1 ARV medications is covered in this review, including new developments in ARV therapy based on the drug's mechanism of action, the challenges related to HIV‐1, and the need for combination therapy. Optimistically, this article will consolidate the overall updates of HIV‐1 ARV treatments and conclude the significance of HIV‐1‐related pharmacotherapy research to combat the global threat of HIV infection.

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Section: Fusion Inhibitorsmentioning

confidence: 99%

Section: Current Hiv‐1 Anti‐retrovirals and The Mechanisms Of Actionmentioning

confidence: 99%

Pharmacological advances in anti‐retroviral therapy for human immunodeficiency virus‐1 infection: A comprehensive review

Azzman,

Gill,

Hassan

et al. 2024

Reviews in Medical Virology

View full text Add to dashboard Cite

show abstract

“…Therefore, it is not surprising that peptides of different lengths, including residues 24 to 53 of the ACE2 receptor, have commonly been reported to exhibit high affinity binding to various regions of the SARS-CoV-2 Spike protein (de Campos et al, 2021;Larue et al, 2021). Many of these peptides, derived from the N-terminal α-helix of ACE2, have been tested in response to the SARS-CoV-2 pandemic (Tzotzos, 2022). Since the SARS-CoV-2 virus enters cells through the interaction between the Spike glycoprotein and ACE2 ectodomain, disrupting the Spike/ ACE2 interaction represents a major target for preventing cell infection (Gheblawi et al, 2020;Papageorgiou and Mohsin, 2020).…”

Section: Introductionmentioning

confidence: 99%

Design of protein-binding peptides with controlled binding affinity: the case of SARS-CoV-2 receptor binding domain and angiotensin-converting enzyme 2 derived peptides

Parisi,

Piacentini,

Incocciati

et al. 2024

Front. Mol. Biosci.

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The development of methods able to modulate the binding affinity between proteins and peptides is of paramount biotechnological interest in view of a vast range of applications that imply designed polypeptides capable to impair or favour Protein-Protein Interactions. Here, we applied a peptide design algorithm based on shape complementarity optimization and electrostatic compatibility and provided the first experimental in vitro proof of the efficacy of the design algorithm. Focusing on the interaction between the SARS-CoV-2 Spike Receptor-Binding Domain (RBD) and the human angiotensin-converting enzyme 2 (ACE2) receptor, we extracted a 23-residues long peptide that structurally mimics the major interacting portion of the ACE2 receptor and designed in silico five mutants of such a peptide with a modulated affinity. Remarkably, experimental KD measurements, conducted using biolayer interferometry, matched the in silico predictions. Moreover, we investigated the molecular determinants that govern the variation in binding affinity through molecular dynamics simulation, by identifying the mechanisms driving the different values of binding affinity at a single residue level. Finally, the peptide sequence with the highest affinity, in comparison with the wild type peptide, was expressed as a fusion protein with human H ferritin (HFt) 24-mer. Solution measurements performed on the latter constructs confirmed that peptides still exhibited the expected trend, thereby enhancing their efficacy in RBD binding. Altogether, these results indicate the high potentiality of this general method in developing potent high-affinity vectors for hindering/enhancing protein-protein associations.

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The Role of Structural Flexibility in Hydrocarbon‐Stapled Peptides Designed to Block Viral Infection via Human ACE2 Mimicry

Jiang,

Tian,

Nicolaescu

et al. 2024

Peptide Science

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The COVID‐19 pandemic drove a uniquely fervent pursuit to explore the potential of peptide, antibody, protein, and small‐molecule‐based antiviral agents against severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). The interaction between the SARS‐CoV2 spike protein with the angiotensin‐converting enzyme 2 (ACE2) receptor that mediates viral cell entry was a particularly interesting target given its well‐described protein–protein interaction (PPI). This PPI is mediated by an α‐helical portion of ACE2 binding to the receptor binding domain (RBD) of the spike protein and thought to be susceptible to blockade through molecular mimicry. Small numbers of hydrocarbon‐stapled synthetic peptides designed to disrupt or block this interaction were tested individually and were found to have variable efficacy despite having related or overlapping sequences and similarly increased α‐helicity. Reasons for these differences are unclear and reported preclinical successes have been limited. This study sought to better understand reasons for these differences through evaluation of a comprehensive collection of hydrocarbon‐stapled peptides, designed based on four distinct principles: stapling position, number of staples, amino acid sequence, and primary sequence length. Surprisingly, we observed that the helicity and amino acid sequence iterations of hydrocarbon‐stapled peptides did not correlate with their bioactivity. Our results highlight the importance of iterative and combinatorial testing of these compounds to determine a configuration that best mimics natural binding and allows for chain flexibility while sacrificing structural helicity.

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Stapled peptides as potential inhibitors of SARS‐CoV‐2 binding to the hACE2 receptor

Cited by 8 publications

References 52 publications

Pharmacological advances in anti‐retroviral therapy for human immunodeficiency virus‐1 infection: A comprehensive review

Pharmacological advances in anti‐retroviral therapy for human immunodeficiency virus‐1 infection: A comprehensive review

Design of protein-binding peptides with controlled binding affinity: the case of SARS-CoV-2 receptor binding domain and angiotensin-converting enzyme 2 derived peptides

The Role of Structural Flexibility in Hydrocarbon‐Stapled Peptides Designed to Block Viral Infection via Human ACE2 Mimicry

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