Plitidepsin’s Significant Potential as a Therapeutic for the Treatment of COVID-19
Nevan Krogan
Professor, UCSF Medical Center
The SARS-CoV-2 coronavirus is reliant on host cell proteins to successfully complete the viral replication cycle. We have previously shown that SARS-CoV-2 viral proteins interact with the eukaryotic translation machinery and that small molecule inhibitors of translation had potent antiviral effects. Here we report that the clinically-approved drug plitidepsin (aplidin) possesses potent antiviral activity (IC90 = 0.88 nM) against SARS-CoV-2 in vitro, with limited toxicity. Through the use of a drug resistant mutant, we also show that the antiviral activity of plitidepsin against SARS-CoV-2 is mediated through inhibition of the known target eEF1A. Finally, we demonstrate the in vivo efficacy of plitidepsin treatment in two animal models of SARS-CoV-2 infection with a reduction of viral replication in the lungs by two orders of magnitude over a three-day period of treatment. Taken together, our results indicate that plitidepsin is an extremely promising candidate for the treatment of COVID19 and should be strongly considered for expanded clinical trials globally.
Nevan Krogan, PhD, is a molecular biologist, UC San Francisco professor, and director of the intensely interdisciplinary Quantitative Biosciences Institute (QBI) under the UCSF School of Pharmacy. He is also a senior investigator at the Gladstone Institutes.
He led the work to create the SARS-CoV-2 interactome and assembled the QBI Coronavirus Research Group (QCRG), which includes hundreds of scientists from around the world. His research focuses on developing and using unbiased, quantitative systems approaches to study a wide variety of diseases with the ultimate goal of developing new therapeutics.
Nevan serves as Director of The HARC Center, an NIH-funded collaborative group that focuses on the structural characterization of HIV-human protein complexes. Dr. Krogan is also the co-Director of three Cell Mapping initiatives, the Cancer Cell Mapping Initiative (CCMI), the Host Pathogen Map Initiative (HPMI) and the Psychiatric Cell Map Initiative (PCMI). These initiatives map the gene and protein networks in healthy and diseased cells with these maps being used to better understand disease and provide novel therapies to fight them.
He has authored over 250 papers in the fields of genetics and molecular biology and has given over 350 lectures and seminars around the world. He is a Searle Scholar, a Keck Distinguished Scholar, and was recently awarded the Roddenberry Prize for Biomedical Research.