CATHEPSIN L INHIBITORS AS PAN CORONAVIRUS THERAPEUTICS

DESCRIPTION provided by applicant Coronaviruses CoV are RNA viruses that cause gastrointestinal respiratory and neurological symptoms in several mammalian species The outbreak of the severe acute respiratory syndrome CoV SARS CoV in humans was fatal in of infected patients infecting people and killing The recent incidents involving the highly pathogenic Middle East Respiratory Syndrome CoV MERS CoV demonstrate that the emergence of pathogenic CoVs from animals to humans can occur at any time There are currently no FDA approved drugs available for treatment of either SARS or MERS thus the development of therapeutic agents to treat CoV infections is an essential unmet medical need Because entry into host cells is the first step in the viral life cycle this aea offers a major target for treatment and prevention CoVs encode three surface proteins and the spike S protein must be proteolyzed by human cathepsin L CatL for proper entry The fact that several CoVs utilize this key human protease CatL for entry offers an opportunity to develop pan anticoronavirus inhibitor drugs We aim to generate potent specific lead inhibitors for CatL via exploration of the prime side a helical binding pocket that results in inhibition of SARS CoV and MERS CoV infection in live cell assays and to analyze ADME toxicology properties en route to testing in animal models of CoV infection PUBLIC HEALTH RELEVANCE Coronaviruses cause gastrointestinal respiratory and neurological symptoms in humans The outbreak of the severe acute respiratory syndrome CoV SARS in humans was fatal in of infected patients infecting people and killing The recent incidents involving the highly pathogenic Middle East Respiratory Syndrome CoV MERS demonstrate that the emergence of pathogenic coronaviruses from animals to humans can occur at any time There are currently no FDA approved drugs available for treatment of either SARS or MERS thus the development of therapeutic agents to treat coronavirus infections is an essential unmet medical need Both viruses require a human enzyme for the completion of the life cycle We aim to generate potent specific lead inhibitors for this enzyme to develop therapeutics for both SARS and MERS infection in people