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

Abstract

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.

ACE2 : S1 RBD Interaction-Targeted Peptides and Small Molecules as Potential COVID-19 Therapeutics

“…In summary, we have described an assay that can quickly and easily screen small molecules or biologics in both low and high throughput fashion. This protocol can be used by other labs in screening not only peptides and small molecules, as we have demonstrated, but many other potential entry inhibitors such as miniproteins and nanobodies [ 58 ]. Importantly, AlphaScreen™ technology is homogeneous, high-throughput, sensitive, versatile, cost-effective, and together with time-resolved Forster resonance energy transfer (TR-FRET, HTRF), it has been very successful at protein-protein interaction-based drug discovery [ 59 , 60 ].…”

A natural broad-spectrum inhibitor of enveloped virus entry, effective against SARS-CoV-2 and Influenza A Virus in preclinical animal models

“…Secondly, since virus entry mechanisms are limited, targeting one of these pathways can in principle inhibit a broad range of viruses that employ similar cellular pathways (Meganck andBaric, 2021, Mazzon andMarsh, 2019b). In the context of COVID-19, entry inhibitors could be used for pre-exposure prophylaxis and to limit the chances of SARS-CoV-2 antigenic drift (Chitsike and Duerksen-Hughes, 2021). Picolinic acid (PA), also known as pyridine-2-carboxylic acid or 2-picolinic acid (PubChem, CID 1018), is a naturally occurring intermediate produced during the catabolism of Tryptophan via the Kynurenine pathway (Melillo et al, 1996, Grant et al, 2009.…”

“…Secondly, since virus entry mechanisms are limited, targeting one of these pathways can in principle inhibit a broad range of viruses that employ similar cellular pathways (Meganck and Baric, 2021, Mazzon and Marsh, 2019b). In the context of COVID-19, entry inhibitors could be used for pre-exposure prophylaxis and to limit the chances of SARS-CoV-2 antigenic drift (Chitsike and Duerksen-Hughes, 2021).…”

Peptides derived from the SARS-CoV-2 receptor binding motif bind to ACE2 but do not block ACE2-mediated host cell entry or pro-inflammatory cytokine induction

“…This association drives high viral infection rates and consequential pathogenic severity [5][6][7][8]. Neutralising antibodies raised against the RBD, soluble recombinant ACE2 (sACE2), and other related proteins have demonstrated a clear ability to block the RBD-ACE2 proteinprotein interaction (PPI) and attenuate viral entry of both SARS-CoV-1 and SARS-CoV-2 strains [9]. These findings highlight the potential of disrupting the RBD-ACE2 protein-protein interaction (PPI) as a promising antiviral therapeutic approach.…”

“…Research aimed at developing viral entry peptide inhibitors by competitively targeting the SARS-CoV-2 -ACE2 molecular interaction, has largely focussed on the antiviral potential of ACE2 sequence derived peptides/peptidomimetics [9]. These studies utilised existing co-crystal structures of ACE2 in complex with SARS-CoV-2 S RBD , to design peptides that contain known RBD contact residues found within the α1 helix of the ACE2 binding interface [16][17][18].…”