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?:abstract
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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 EC50 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 pKa 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
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