The main objective of this project is to advance our extensive preliminary results and develop
novel protease inhibitor drugs for the effective treatment of COVID-19. The COVID-19 pandemic,
caused by the highly transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-
2), emerged in central China's Hubei Province, Wuhan in December 2019. The outbreak has
spread at an alarming rate, creating a catastrophic global health crisis the likes of which the world
has not witnessed in over 100 years. SARS-CoV-2 has spread to nearly every continent around
the globe and has affected over 4.8 million individuals with more than 380,000 deaths. Thus far,
there are no vaccines or approved effective drug treatments against COVID-19. The development
of antiviral agents is the foremost priority for reducing morbidity and mortality around the world.
SARS-CoV-2 encodes two classes of cysteine proteases, the 3-chymotrypsin-like protease
(3CLpro) and the papain-like protease (PLpro), which are critical for coronavirus replication.
These two proteases have been recognized as important targets for drug development against
COVID-19 and related pathogenic coronaviruses.
In our extensive collaborative work against SARS and MERS coronaviruses, we previously
developed and reported the development of a variety of covalent and non-covalent small-
molecule reversible inhibitors of SARS-CoV-3CLpro that showed significant antiviral activity. We
also demonstrated that PLpro is a significant drug target by developing the first non-covalent,
reversible and potent inhibitors of SARS-CoV-PLpro that show effective antiviral activity in cell
culture and in an animal model. We carried out structure-activity and extensive X-ray structural
studies to gain molecular insight into the 3CLpro and PLpro active sites of SARS, MERS and
most recently SARS-CoV-2. Furthermore, we have now generated a number of new small
molecule lead inhibitors of SARS-CoV-2 3CLpro and PLpro and determined several high-
resolution X-ray structures of SARS-CoV-2 3CLpro inhibitor complexes. This work forms the basis
of our proposed studies. We now plan to design, optimize and develop structurally novel drug-
like and broad-spectrum protease inhibitors that show favorable pharmacological profiles and low
toxicity. We will carry out a multidisciplinary research effort that will integrate X-ray structure-
guided design, iterative medicinal chemistry, molecular modeling, biochemical and biophysical
assays, antivirus and cell biological studies in combination with various physiochemical assays to
optimize compounds for preclinical development against COVID-19.