R01AI158649

SARS-CoV-2 Protease Inhibitors for Treating COVID-19 - Abstract

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, antiviral and cell biological studies in combination with various physiochemical assays to optimize compounds for preclinical development against COVID-19.

Purdue University

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

West Lafayette, Indiana 479072084 United States

Single Zip Code

Emergency Awards: Rapid Investigation of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19) (R01 Clinical Trial Not Allowed) (PAR-20-178)

COVID-19 $1,501,948 (50%) percent of this Project Grant was funded by COVID-19 emergency acts including the American Rescue Plan Act of 2021.
Amendment Since initial award the End Date has been extended from 07/31/26 to 07/31/27 and the total obligations have increased 300% from $750,974 to $3,003,896.