Rationally Designed ACE2-Derived Peptides Inhibit SARS-CoV-2

Abstract

Severe acute respiratory syndrome coronavirus (SARS-CoV)-2 is a novel and highly pathogenic coronavirus and is the causative agent of the coronavirus disease 2019 (COVID-19). The high morbidity and mortality associated with COVID-19 and the lack of an approved drug or vaccine for SARS-CoV-2 underscores the urgent need for developing effective antiviral therapies. Therapeutics that target essential viral proteins are effective at controlling virus replication and spread. Coronavirus Spike glycoproteins mediate viral entry and fusion with the host cell, and thus are essential for viral replication. To enter host cells, the Spike proteins of SARS-CoV-2 and related coronavirus, SARS-CoV, bind the host angiotensin-converting enzyme 2 (ACE2) receptor through their receptor binding domains (RBDs). Here, we rationally designed a panel of ACE2-derived peptides based on the RBD-ACE2 binding interfaces of SARS-CoV-2 and SARS-CoV. Using SARS-CoV-2 and SARS-CoV Spike-pseudotyped viruses, we found that a subset of peptides inhibits Spike-mediated infection with IC 50 values in the low millimolar range. We identified two peptides that bound Spike RBD in affinity precipitation assays and inhibited infection with genuine SARS-CoV-2. Moreover, these peptides inhibited the replication of a common cold causing coronavirus, which also uses ACE2 as its entry receptor. Results from the infection experiments and modeling of the peptides with Spike RBD identified a 6-amino-acid (Glu37-Gln42) ACE2 motif that is important for SARS-CoV-2 inhibition. Our work demonstrates the feasibility of inhibiting SARS-CoV-2 with peptide-based inhibitors. These findings will allow for the successful development of engineered peptides and peptidomimetic-based compounds for the treatment of COVID-19.

Molecular Recognition of SARS-CoV-2 Spike Glycoprotein: Quantum Chemical Hot Spot and Epitope Analyses

“…These results are consistent with previous ndings 2, 17,28,80 in Section S5. † We also discovered 17 and 4 new hot spots of the SARS-CoV-2 S-protein and the ACE2, respectively (Fig.…”

“…S6 †). It was conrmed that the N501Y mutation of the S-protein attractively enhances the DI energy of Y41 ACE2 on the peptide motif (E37-Q42), which was essential for recognizing the S-protein, as proposed by Larue et al 28 Along with these attractive interactions, it was conrmed that the binding energy including both statistical correction and desolvation (SC+Desolv) of the ACE2 with the mutant S-protein (N501Y) was further strengthened by ca. À10 kcal mol À1 compared to that with the wild type S-protein as seen in Tables 1 and S6.…”

“…[17][18][19] Molecular dynamics (MD) simulations for the complex formed by the Sprotein and ACE2 were conducted to better understand their association. [20][21][22][23][24][25][26] Approaches for drug/neutralizing antibody design targeting S-protein have been reported, such as a de novo design peptide inhibitors for SARS-CoV-2, 27,28 a virtual screening of antiviral compounds for the SARS-CoV-2 ( ref. 29 ) and sequencebased epitope analysis for the SARS-CoV-2, among others.…”

Natural variants in SARS-CoV-2 Spike protein pinpoint structural and functional hotspots with implications for prophylaxis and therapeutic strategies

“…Preventing proteolysis of the S protein 10 ; (2). Competing with S1 binding to hACE2, using S1 or hACE2 protein fragments or peptides 1 , 11 , 12 ; (3). Generating monoclonal or polyclonal antibodies against SARS-CoV-2 S protein or RBD, to be used as passive vaccines 13 ; and (4) Active vaccines that generate an immune response, usually to the S1 subunit 14 – 16 .…”

ENNAVIA is an innovative new method which employs neural networks for antiviral and anti-coronavirus activity prediction for therapeutic peptides

“…This class of potential antiviral agents possesses a number of advantages over conventional non-peptide drugs, as they are highly specific, costeffective to produce while remaining easy to modify and synthesise, and possess a limited susceptibility to drug resistance [12] . Although initially AVPs were isolated from plant and animal secretions where they formed part of the host defence mechanism [13] , AVPs have also been derived from chemical [14] , genetic [15] and recombinant [16] libraries, as well as from rational design [17] . AVPs can be divided into two classes based on their mechanism of action: virus-targeting and host-targeting [18] .…”