Virtual and In Vitro Antiviral Screening Revive Therapeutic Drugs for COVID-19

Abstract

The urgent need for a cure for early phase COVID-19 infected patients critically underlines drug repositioning strategies able to efficiently identify new and reliable treatments by merging computational, experimental, and pharmacokinetic expertise. Here we report new potential therapeutics for COVID-19 identified with a combined virtual and experimental screening strategy and selected among already approved drugs. We used hydroxychloroquine (HCQ), one of the most studied drugs in current clinical trials, as a reference template to screen for structural similarity against a library of almost 4000 approved drugs. The top-ranked drugs, based on structural similarity to HCQ, were selected for in vitro antiviral assessment. Among the selected drugs, both zuclopenthixol and nebivolol efficiently block SARS-CoV-2 infection with EC 50 values in the low micromolar range, as confirmed by independent experiments. The anti-SARS-CoV-2 potential of ambroxol, amodiaquine, and its active metabolite ( N -monodesethyl amodiaquine) is also discussed. In trying to understand the “hydroxychloroquine” mechanism of action, both p K a and the HCQ aromatic core may play a role. Further, we show that the amodiaquine metabolite and, to a lesser extent, zuclopenthixol and nebivolol are active in a SARS-CoV-2 titer reduction assay. Given the need for improved efficacy and safety, we propose zuclopenthixol, nebivolol, and amodiaquine as potential candidates for clinical trials against the early phase of the SARS-CoV-2 infection and discuss their potential use as adjuvant to the current (i.e., remdesivir and favipiravir) COVID-19 therapeutics.

Head-to-Head Comparison of Sedation and Somnolence Among 37 Antipsychotics in Schizophrenia, Bipolar Disorder, Major Depression, Autism Spectrum Disorders, Delirium, and Repurposed in COVID-19, Infectious Diseases, and Oncology From the FAERS, 2004–2020

“…Zuclopenthixol, the neuroleptic with the strongest association with sedation and somnolence, has emerged as a compound that shows in vitro inhibition of the severe acute respiratory coronavirus 2 (SARS-CoV-2) pathogen which causes the novel coronavirus disease 2019 (COVID-19) ( Bocci et al, 2020 ). A recent review article reported thioridazine, fluphenazine, perphenazine, chlorpromazine, prochlorperazine inhibits RNA viruses as these phenothiazines inhibit cell-cell fusion, viral replication, clathrin-dependent endocytosis, and entry into cells ( Otręba et al, 2020 ).…”

Targeting the Complement Serine Protease MASP-2 as a Therapeutic Strategy for Coronavirus Infections

“…As a small-molecule antiviral agent, tegobuvir has been evaluated in clinical trials for COVID-19 [ 38 ], while bisoxatin (DB09219) has been suggested as a potential inhibitor of SARS-CoV-2 spike protein following a computational approach [ 39 ]. Amodiaquine has been found to inhibit SARS-CoV-2 replication in vitro [ 40 ], ketanserin has been suggested as a potential additive drug to improve the ventilation/perfusion mismatch in patients with COVID-19 [ 41 ] and, finally, the anti-HIV drug raltegravir has been proposed as a potential 3CL pro inhibitor following a computational approach [ 42 ].…”

COVID-19: A Catalyst for Novel Psychiatric Paradigms - Part 1

“…Several psychotropic drugs have been associated with antiviral and antitumor properties, suggesting that they may lower the severity of COVID-19 critical illness [16]. For example, imipramine, clomipramine and the phenothiazine class of drugs have demonstrated efficacy against other viruses, including Ebola, Dengue and West Nile [17][18][19][20]. In addition, thioridazine, another phenothiazine, was found to slow the progression of lung cancers, probably by enhancing antitumor immunity [21].…”