ABSTRACT
Analysis of the SARS-CoV-2 sequence revealed a multibasic furin cleavage site at the S1/S2 boundary of the spike protein distinguishing this virus from SARS-CoV. Furin, the best-characterized member of the mammalian proprotein convertases, is an ubiquitously expressed single pass type 1 transmembrane protein. Cleavage of SARS-CoV-2 spike protein by furin promotes viral entry into lung cells. While furin knockout is embryonically lethal, its knockout in differentiated somatic cells is not, thus furin provides an exciting therapeutic target for viral pathogens including SARS-CoV-2 and bacterial infections. Several peptide-based and small-molecule inhibitors of furin have been recently reported, and select cocrystal structures have been solved, paving the way for further optimization and selection of clinical candidates. This perspective highlights furin structure, substrates, recent inhibitors, and crystal structures with emphasis on furin's role in SARS-CoV-2 infection, where the current data strongly suggest its inhibition as a promising therapeutic intervention for SARS-CoV-2.
Subject(s)
Antiviral Agents/pharmacology , Furin/antagonists & inhibitors , Peptides/pharmacology , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Animals , Antiviral Agents/chemistry , COVID-19/metabolism , Furin/metabolism , Humans , Peptides/chemistry , SARS-CoV-2/metabolism , Small Molecule Libraries/chemistry , Spike Glycoprotein, Coronavirus/metabolism , COVID-19 Drug TreatmentABSTRACT
Novel beta-coronavirus SARS-CoV-2 is the pathogenic agent responsible for coronavirus disease-2019 (COVID-19), a globally pandemic infectious disease. Due to its high virulence and the absence of immunity among the general population, SARS-CoV-2 has quickly spread to all countries. This pandemic highlights the urgent unmet need to expand and focus our research tools on what are considered "neglected infectious diseases" and to prepare for future inevitable pandemics. This global emergency has generated unprecedented momentum and scientific efforts around the globe unifying scientists from academia, government and the pharmaceutical industry to accelerate the discovery of vaccines and treatments. Herein, we shed light on the virus structure and life cycle and the potential therapeutic targets in SARS-CoV-2 and briefly refer to both active and passive immunization modalities, drug repurposing focused on speed to market, and novel agents against specific viral targets as therapeutic interventions for COVID-19.