Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region

Abstract

The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In the light of the urgent need to identify novel approaches to be used in the emergency phase, a largely explored strategy has been the repurpose of clinically available drugs as new antivirals, by targeting different viral proteins. In this paper, we describe a drug repurposing strategy based on a virtual screening of druggable pockets located in the central -sheet core of the SARS-CoV-2 Spike protein RBD supported by in vitro tests identifying several steroidal derivatives as SARS-CoV-2 entry inhibitors. Our results demonstrate that several potential binding sites exist in the SARS CoV-2 S protein, and that the occupancy of these pockets reduces the ability of the S protein RBD to bind to the ACE2 consensus in vitro. In particular, natural occurring and clinically available steroids as glycyrrhetinic and oleanolic acids, as well as the bile acids derivatives glyco-UDCA and obeticholic acid have been shown to be effective in preventing virus entry in the case of low viral load. All together, these results might help to define novel approaches to reduce the viral load by using SARS-CoV-2 entry inhibitors.

Hijacking SARS-CoV-2/ACE2 Receptor Interaction by Natural and Semi-synthetic Steroidal Agents Acting on Functional Pockets on the Receptor Binding Domain

“…Authors wish to thank all the donors for the kind collaboration. This manuscript has been released as a PrePrint (Carino et al, 2020).…”

A comprehensive guide to the pharmacologic regulation of angiotensin converting enzyme 2 (ACE2), the SARS-CoV-2 entry receptor

“…Importantly, MRBs such as spironolactone possess a significant anti-androgenic activity, which may be beneficial in the context of SARS-CoV-2 infection, by inhibiting the androgen-dependent expression of “Transmembrane protease, serine 2” (TMPRSS2), a transmembrane protease crucial for SARS-CoV-2 entry ( Liaudet & Szabo, 2020 ). In addition, potassium canrenoate (the active metabolite of spironolactone) results in concentration (0.1-10 μM)-dependent reductions of the binding of the SARS-CoV-2 spike protein to the ACE2 receptor ( Carino et al, 2020 ). Increased plasma aldosterone levels associated with disease severity in COVID-19 patients ( Villard et al, 2020 ) suggest that MRBs may have beneficial effects in COVID-19.…”

“…At clinically relevant concentrations, cortisone increases the replication of infectious bronchitis HCoV in tracheal organ cultures, whereas reproductive hormones, such as progesterone, estrogen, and testosterone, do not have this effect ( Ambali & Jones, 1990 ). In a recent in vitro study, steroids (glycyrrhetinic, oleanolic acid) and bile acid derivatives inhibited binding of the SARS-CoV-2 spike protein to ACE2 ( Carino et al, 2020 ). It was also reported that Ciclesonide, an inhaled corticosteroid, suppresses the replication of SARS-CoV-2 with an EC 90 of 0.55 μM in human bronchial epithelial cells ( Matsuyama et al, 2020 ).…”

Food and COVID-19: Preventive/Co-therapeutic Strategies Explored by Current Clinical Trials and in Silico Studies

“…This binding is based on hydrophobic and polar interactions with the steroidal scaffold of glycyrrhetinic acid and further reinforced by many ion and hydrogen interactions. The ability of the most active compounds to prevent virus entry in the case of low viral load was further confirmed in an in vitro study [ 94 ].…”