PT - JOURNAL ARTICLE AU - Sandeep Kumar AU - Jinmei Li AU - Jiwoong Park AU - Sydney K. Hart AU - Niki J. Song AU - Damon T. Burrow AU - Nicholas L. Bean AU - Nicholas C. Jacobs AU - Ariella Coler-Reilly AU - Anastasiia Onyshchenko Pendergrass AU - Tanya H. Pierre AU - India C. Bradley AU - Jan E. Carette AU - Malini Varadarajan AU - Thijn R. Brummelkamp AU - Roland Dolle AU - Tim R. Peterson TI - Sphingolipid Biosynthesis Inhibition As A Host Strategy Against Diverse Pathogens AID - 10.1101/2020.04.10.035683 DP - 2020 Jan 01 TA - bioRxiv PG - 2020.04.10.035683 4099 - http://biorxiv.org/content/early/2020/04/14/2020.04.10.035683.short 4100 - http://biorxiv.org/content/early/2020/04/14/2020.04.10.035683.full AB - Chloroquine is an anti-malarial and immunosuppressant drug that has cationic amphipathic chemical properties. We performed genome-wide screens in human cells with chloroquine and several other widely used cationic amphipathic drugs (CADs) including the anti-depressants, sertraline (Zoloft) and fluoxetine (Prozac), the analgesic nortriptyline (Pamelor), the anti-arrhythmic amiodarone (Cordarone), and the anti-hypertensive verapamil (Calan) to characterize their molecular similarities and differences. Despite CADs having different disease indications but consistent with them sharing key chemical properties, we found CADs to have remarkably similar phenotypic profiles compared with non-CADs we and others have previously screened (1–5). The most significant genetic interaction for all CADs was the initiating step in sphingolipid biosynthesis catalyzed by serine palmitoyltransferase (SPT). A comparison of genome-wide screens performed with diverse pathogens from viruses, bacteria, plants, and parasites including Ebola (6), adeno-associated virus AAV2 (7), HIV (8), Rotavirus (9), Influenza A (10), Zika virus (11), Picornavirus (12), Exotoxin A (13), Cholera toxin (14), Type III secretion system and Shiga toxin (15, 16), Ricin toxin (17), and Toxoplasma gondii (18) showed SPT as a top common host factor and 80% overlap overall in top hits specifically with CADs. Potential sphingolipid-mediated mechanisms for the host response- and virulence-modulating effects of CADs involve autophagy and SERPINE1/PAI-1 (plasminogen activator inhibitor-1). Chloroquine has recently shown potential as an anti-viral agent for the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease (19, 20). Our study demonstrates that numerous readily available drugs molecularly function highly similar to chloroquine, which suggests they might be considered for further pre-clinical investigation in the context of SARS-CoV-2. More generally, our work suggests the diverse pathogen mitigating potential of drugs that inhibit host sphingolipid biosynthesis such as CADs.Brief Summary Our study demonstrates that numerous readily available drugs molecularly function highly similar to chloroquine, which suggests they might be considered for further pre-clinical investigation in the context of SARS-CoV-2.Competing Interest StatementThe corresponding author, Timothy R Peterson, is the founder of Bio-I/O, a St. Louis-based biotech company specializing in drug target identification. Bio-I/O is the recipient of NIH/NIDDK funding (R42 DK121652), which is focused on different drugs than those studied herein, but is still in the space of drug target ID.CADscationic amphipathic (amphiphilic) drugs, also known as lysosomotropic agentsSARS-CoV-1Severe acute respiratory syndrome coronavirus-1SARS-CoV-2Severe acute respiratory syndrome coronavirus-2COVID-19Coronavirus Disease-2019 where SARS-CoV-2 is the causative agentFDAUS Food and Drug AdministrationMOAmechanism of actionSPTserine palmitoyltransferaseSPTLC2serine palmitoyltransferase long chain base subunit 2COGconserved oligomeric golgi complexGARPgolgi-associated retrograde protein complexSERPINE1/PAI-1serine protease inhibitor (SERPIN) Family E Member 1/plasminogen activator inhibitor-1