Antiviral drugs targeting endosomal membrane proteins inhibit distant animal and human pathogenic viruses

The endocytic pathway is a common strategy that several highly pathogenic viruses use to enter into the cell. To demonstrate the usefulness of this pathway as a common target for the development of broad-spectrum antivirals, the inhibitory effect of drug compounds targeting endosomal membrane proteins were investigated. This study entailed direct comparison of drug effectiveness against animal and human pathogenic viruses, namely Ebola (EBOV), African swine fever virus (ASFV), and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A panel of experimental and FDA-approved compounds targeting calcium channels and PIKfyve at the endosomal membrane caused potent reductions of entry up to 90% in SARS-CoV-2 S-protein pseudotyped retrovirus. Similar inhibition was observed against transduced EBOV glycoprotein pseudovirus and ASFV. SARS-CoV-2 infection was potently inhibited by selective estrogen receptor modulators in cells transduced with pseudovirus, among them Raloxifen inhibited ASFV with very low 50% inhibitory concentration. Finally, the mechanism of the inhibition caused by the latter in ASFV infection was analyzed. Overall, this work shows that cellular proteins related to the endocytic pathway can constitute suitable cellular targets for broad range antiviral compounds. [Display omitted] •Targeting the endocytic pathway can be a common antiviral strategy against distant animal and human pathogenic viruses.•Compounds targeting endosomal calcium channels and PIKfyve enzyme, inhibited entry of these viruses with similar potency.•SERMS TMX and RLX caused marked infectivity reductions, obtaining for RLX an IC50 of 0.91 inhibiting ASFV.•The mechanism of action of SERMS on ASFV was not due to their action on the estrogen receptor pathway.•SERMS inhibited ASFV infectivity acting at the endosomal flux of calcium and cholesterol.