Stapled <scp>ACE2</scp> peptidomimetics designed to target the <scp>SARS‐CoV</scp>‐2 spike protein do not prevent virus internalization

Morgan, Danielle C.; Morris, Caroline; Mahindra, Amit; Blair, Connor M.; Tejeda, Gonzalo S.; Herbert, Imogen; Turnbull, Matthew L.; Lieber, Gauthier; Willett, Brian J.; Logan, Nicola; Smith, Brian; Tobin, Andrew B.; Bhella, David; Baillie, George S.; Jamieson, Andrew G.

doi:10.1002/pep2.24217

Cited by 41 publications

(57 citation statements)

References 30 publications

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“…However, the last study pointed out that mono-stapled peptides can successfully constrained α-helical structure in solution but do not prevent virus internalization. Thus, according to the suggestion by Morgan et al, 42 the double stapling is a viable approach for inducing α1-helicity, which may prevent virus internalization as described by Curreli et al. 40 when smaller peptides (∼30 mer) are evaluated.…”

Section: Results and Discussionmentioning

confidence: 99%

“… 41 Their lead peptide presented increased affinity for the RBD (IC 50 : 3.6 μM, K D : 2.1 μM) compared with the control group; a 35-mer sequence extracted from the hACE2. In contrast, Morgan et al reported that their 23-mer mono-stapled peptides effectively constrained the helical structure in solution, but none of those peptides prevented virus internalization, 42 which indicates that must be an optimal peptide length and number/position of the staples to reach antiviral activity. Moreover, these results agree and validate our theory that using stapled peptides derived from the α1 helix of hACE2 could lay the foundations for further optimization of a potential clinical candidate.…”

Section: Introductionmentioning

confidence: 95%

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Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An In Silico Study

2021

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a pandemic of unprecedented scale. This coronavirus enters cells by the interaction of the receptor binding domain (RBD) with the human angiotensin-converting enzyme 2 receptor (hACE2). In this study, we employed a rational structure-based design to propose 22-mer stapled peptides using the structure of the hACE2 α1 helix as a template. These peptides were designed to retain the α-helical character of the natural structure, to enhance binding affinity, and to display a better solubility profile compared to other designed peptides available in the literature. We employed different docking strategies (PATCHDOCK and ZDOCK) followed by a double-step refinement process (FIBERDOCK) to rank our peptides, followed by stability analysis/evaluation of the interaction profile of the best docking predictions using a 500 ns molecular dynamics (MD) simulation, and a further binding affinity analysis by molecular mechanics with generalized Born and surface area (MM/GBSA) method. Our most promising stapled peptides presented a stable profile and could retain important interactions with the RBD in the presence of the E484K RBD mutation. We predict that these peptides can bind to the viral RBD with similar potency to the control NYBSP-4 (a 30-mer experimentally proven peptide inhibitor). Furthermore, our study provides valuable information for the rational design of double-stapled peptide as inhibitors of SARS-CoV-2 infection.

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Section: Results and Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An In Silico Study

2021

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“…The crystal structure S-RBD/ACE2 complex solution triggered the drug-discovery efforts to discover entry inhibitors, including peptide analogs, monoclonal antibodies, and protein chimeras (38)(39)(40)(41)(42)(43)(44)(45)(46). Despite these new technologies and macromolecules as therapeutic agents, small molecules remain the preferred choice for drug development due to their better pharmacokinetic profile, stability, and dosage logistics (47,48).…”

Section: Discussionmentioning

confidence: 99%

Discovery and Evaluation of Entry Inhibitors for SARS-CoV-2 and Its Emerging Variants

Acharya

Pandey

Thurman

et al. 2021

J Virol

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The outbreak of SARS-CoV-2 is responsible for the COVID-19 pandemic. Despite unprecedented research and developmental efforts, SARS-CoV-2-specific antivirals are still unavailable for the treatment of COVID-19. In most instances, SARS-CoV-2 infection initiates with the binding of spike glycoprotein to the host cell ACE2 receptor. Utilizing the crystal structure of the ACE2/Spike receptor-binding domain (S-RBD) complex (PDB file 6M0J) in a computer-aided drug design (CADD) approach, we identified and validated 5 potential inhibitors of S-RBD and ACE-2 interaction. Two of the five compounds, MU-UNMC-1 and MU-UNMC-2, blocked the entry of pseudovirus particles expressing SARS-CoV-2 Spike glycoprotein. In live SARS-CoV-2 infection assays, both the compounds showed antiviral activity with IC 50 values in the micromolar range (MU-UNMC-1: IC 50 = 0.67 μM and MU-UNMC-2: IC 50 = 1.72 μM) in human bronchial epithelial cells. Furthermore, MU-UNMC-1 and MU-UNMC-2 effectively blocked the replication of rapidly transmitting variants of concern: South African variant B.1.351 (IC 50 = 9.27 μM & 3.00 μM) and Scotland variant B.1.222 (IC 50 = 2.64 μM & 1.39 μM) respectively. Following these assays, we conducted ‘induced-fit (flexible) docking’ to understand the binding mode of MU-UNMC-1/MU-UNMC-2 at the S-RBD/ACE2 interface. Our data showed that mutation N501Y (present in B.1.351 variant) alters the binding mode of MU-UNMC-2 such that it is partially exposed to the solvent and has reduced polar contacts. Finally, MU-UNMC-2 displayed high synergy with remdesivir (RDV), the only approved drug for treating hospitalized COVID-19 patients. IMPORTANCE The ongoing coronavirus infectious disease 2019 (COVID-19) pandemic is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More than 207 million people have been infected globally, and 4.3 million have died due to this viral outbreak. While a few vaccines have been deployed, a SARS-CoV-2 specific antiviral for the treatment of COVID-19 is yet to be approved. As the interaction of SARS-CoV-2 spike protein with ACE2 is critical for cellular entry, using a combination of a computer-aided drug design (CADD) approach and cell-based in vitro assays, we report the identification of five potential SARS-CoV-2 entry inhibitors. Out of the five, two compounds (MU-UNMC-1 and MU-UNMC-2) have antiviral activity against ancestral SARS-CoV-2 and emerging variants from South Africa and Scotland. Furthermore, MU-UNMC-2 acts synergistically with remdesivir, suggesting that RDV and MU-UNMC-2 can be developed as a combination therapy to treat COVID-19, infected individuals.

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“…Certainly, an argument can be made that the lack of binding here may be due to limited secondary structure in solution of the linear native peptide designed by Zhang et al [113]. Nonetheless, a different group has shown that even with stapling that dramatically improved helicity of their peptides, no appreciable binding activity was observed for either stabilized and non-stabilized peptides [123]. In our lab we have found that peptides rationally designed from the binding motifs of either ACE2 or S1 RBD display modest inhibitory activity in the low micromolar range (unpublished).…”

Section: S1 and S2 Targeted Peptidesmentioning

confidence: 95%

Keep out! SARS-CoV-2 entry inhibitors: their role and utility as COVID-19 therapeutics

Chitsike

Duerksen-Hughes

2021

Virol J

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The COVID-19 pandemic has put healthcare infrastructures and our social and economic lives under unprecedented strain. Effective solutions are needed to end the pandemic while significantly lessening its further impact on mortality and social and economic life. Effective and widely-available vaccines have appropriately long been seen as the best way to end the pandemic. Indeed, the current availability of several effective vaccines are already making a significant progress towards achieving that goal. Nevertheless, concerns have risen due to new SARS-CoV-2 variants that harbor mutations against which current vaccines are less effective. Furthermore, some individuals are unwilling or unable to take the vaccine. As health officials across the globe scramble to vaccinate their populations to reach herd immunity, the challenges noted above indicate that COVID-19 therapeutics are still needed to work alongside the vaccines. Here we describe the impact that neutralizing antibodies have had on those with early or mild COVID-19, and what their approval for early management of COVID-19 means for other viral entry inhibitors that have a similar mechanism of action. Importantly, we also highlight studies that show that therapeutic strategies involving various viral entry inhibitors such as multivalent antibodies, recombinant ACE2 and miniproteins can be effective not only for pre-exposure prophylaxis, but also in protecting against SARS-CoV-2 antigenic drift and future zoonotic sarbecoviruses.

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Stapled ACE2 peptidomimetics designed to target the SARS‐CoV‐2 spike protein do not prevent virus internalization

Cited by 41 publications

References 30 publications

Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An In Silico Study

Targeting SARS-CoV-2 Receptor Binding Domain with Stapled Peptides: An In Silico Study

Discovery and Evaluation of Entry Inhibitors for SARS-CoV-2 and Its Emerging Variants

Keep out! SARS-CoV-2 entry inhibitors: their role and utility as COVID-19 therapeutics

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