A screen of the NIH Clinical Collection small molecule library identifies potential anti-coronavirus drugs

Abstract

With the recent emergence of Middle East Respiratory Syndrome coronavirus in humans and the outbreak of devastating porcine epidemic diarrhea coronavirus in swine, therapeutic intervention is urgently needed. However, anti-coronavirus drugs currently are not available. In an effort to assist rapid development of anti-coronavirus drugs, here we screened the NIH Clinical Collection in cell culture using a luciferase reporter-expressing recombinant murine coronavirus. Of the 727 compounds screened, 84 were found to have a significant anti-coronavirus effect. Further experiments revealed that 51 compounds blocked virus entry while 19 others inhibited viral replication. Additional validation studies with the top 3 inhibitors (hexachlorophene, nitazoxanide and homoharringtonine) demonstrated robust anti-coronavirus activities (a reduction of 6 to 8log10 in virus titer) with an IC50 ranging from 11nM to 1.2μM. Furthermore, homoharringtonine and hexachlorophene exhibited broad antiviral activity against diverse species of human and animal coronaviruses. Since the NIH Clinical Collection consists of compounds that have already been through clinical trials, these small molecule inhibitors have a great potential for rapid development as anti-coronavirus drugs.

Influences of cyclosporin A and non-immunosuppressive derivatives on cellular cyclophilins and viral nucleocapsid protein during human coronavirus 229E replication

“…The first four viruses mainly target the respiratory tract and are associated with common colds, whereas SARS-and MERS-CoV are highly pathogenic with high mortality rates (Cui et al, 2019). Although great efforts have been made to discover anti-MERS agents by screening defined drug libraries (Cao et al, 2015;de Wilde et al, 2014;Dyall et al, 2014;LaFemina, 2014) no effective drug treatment is available against CoVs.…”

Drug repurposing for new, efficient, broad spectrum antivirals

“…With different mechanisms of action, digoxin, sunitinib, chloroquine, cyclosporine A and silver nanoparticles are promising candidates for broad spectrum antivirals that could be used in a combined antiviral therapy. Drug repurposing is now facilitated by a number of resources (Pollastri and Campbell, 2011), such as pathogen target bioinformatics resources, public data repositories of screening data, structural biology resources and compound collections, such as the library of small molecules from the National Institutes of Health (http://www.nihclinicalcollection.com) (Ashbrook et al, 2016;Cao et al, 2015) or the Canadian DrugBank (https://www.drugbank. ca/), a large drug database commonly used by computational drug repositioning methods.…”

Targeting the β‐clamp in Helicobacter pylori with FDA‐approved drugs reveals micromolar inhibition by diflunisal

“…Schrodinger's Protein Preparation Wizard was used to remove water and sulphate molecules and to add hydrogen atoms followed by minimization and optimization for inhibitor screening. A library of molecules was generated that consisted of FDA‐approved drugs from several databases, including DrugBank , e‐LEA3D , NIH Clinical Collection , the binding database (BindingDB) , Therapeutic target database , Virtual library repository (http://rocce-vm0.ucsd.edu/data/sw/hosted/virtuallib/), Maybridge HitFinder (http://www.maybridge.com) and Selleckchem (http://www.selleckchem.com). The set of FDA‐approved drugs consisted of thousands of molecules.…”