R01AI168165
Project Grant
Overview
Grant Description
Targeting SARS-CoV-2 PLpro for COVID-19 Treatment - Abstract
The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused profound socioeconomic challenges for humankind. Antiviral agents blocking SARS-CoV-2 viral replication that complement vaccination are urgently needed to stop the current pandemic and to avoid potential future outbreaks.
The papain-like protease (PLpro), an essential cysteine protease that regulates viral replication and host immune sensing, is a promising antiviral target against SARS-CoV-2. However, the rapid development of potent PLpro inhibitors has been hindered by limited draggable interactions at the active site due to restricted P1 and P2 sites with glycine recognition.
To address these challenges, we have investigated novel, druggable binding sites, distal to the active site, using structure-guided design and X-ray crystallography. These efforts led to a series of 2-phenylthiophene-based inhibitors with low nanomolar potency. Crystal structures revealed that these potent SARS-CoV-2 PLpro inhibitors engage with a novel ligand-binding site, the "BL2 groove," leading to slower off-rates, improved binding affinities, and low micromolar antiviral potency in SARS-CoV-2-infected human cells.
Moreover, these inhibitors showed good microsomal stability and in vivo exposure after intraperitoneal (IP) administration. Building on these encouraging preliminary data, we propose in this project to further optimize and develop these novel PLpro inhibitors to achieve in vivo antiviral efficacy.
We propose:
Aim 1) To optimize our lead PLpro inhibitors for improved potency and drug-likeness properties using structure-guided design.
Aim 2) To evaluate and triage PLpro inhibitors based on biochemical, ADME, and antiviral assays.
Aim 3) To assess the PK/PD profile of top inhibitors and to establish in vivo antiviral efficacy.
Completion of the research will lead to small molecules suitable for development as drug candidates to treat SARS-CoV-2.
The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused profound socioeconomic challenges for humankind. Antiviral agents blocking SARS-CoV-2 viral replication that complement vaccination are urgently needed to stop the current pandemic and to avoid potential future outbreaks.
The papain-like protease (PLpro), an essential cysteine protease that regulates viral replication and host immune sensing, is a promising antiviral target against SARS-CoV-2. However, the rapid development of potent PLpro inhibitors has been hindered by limited draggable interactions at the active site due to restricted P1 and P2 sites with glycine recognition.
To address these challenges, we have investigated novel, druggable binding sites, distal to the active site, using structure-guided design and X-ray crystallography. These efforts led to a series of 2-phenylthiophene-based inhibitors with low nanomolar potency. Crystal structures revealed that these potent SARS-CoV-2 PLpro inhibitors engage with a novel ligand-binding site, the "BL2 groove," leading to slower off-rates, improved binding affinities, and low micromolar antiviral potency in SARS-CoV-2-infected human cells.
Moreover, these inhibitors showed good microsomal stability and in vivo exposure after intraperitoneal (IP) administration. Building on these encouraging preliminary data, we propose in this project to further optimize and develop these novel PLpro inhibitors to achieve in vivo antiviral efficacy.
We propose:
Aim 1) To optimize our lead PLpro inhibitors for improved potency and drug-likeness properties using structure-guided design.
Aim 2) To evaluate and triage PLpro inhibitors based on biochemical, ADME, and antiviral assays.
Aim 3) To assess the PK/PD profile of top inhibitors and to establish in vivo antiviral efficacy.
Completion of the research will lead to small molecules suitable for development as drug candidates to treat SARS-CoV-2.
Awardee
Funding Goals
NOT APPLICABLE
Grant Program (CFDA)
Awarding / Funding Agency
Place of Performance
Tucson,
Arizona
85721
United States
Geographic Scope
Single Zip Code
Related Opportunity
Analysis Notes
Amendment Since initial award the total obligations have increased 374% from $682,484 to $3,234,709.
University Of Arizona was awarded
Developing Novel SARS-CoV-2 PLpro Inhibitors for COVID-19 Treatment
Project Grant R01AI168165
worth $3,234,709
from the National Institute of Allergy and Infectious Diseases in February 2022 with work to be completed primarily in Tucson Arizona United States.
The grant
has a duration of 5 years and
was awarded through assistance program 93.855 Allergy and Infectious Diseases Research.
The Project Grant was awarded through grant opportunity NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed).
Status
(Ongoing)
Last Modified 6/5/26
Period of Performance
2/22/22
Start Date
1/31/27
End Date
Funding Split
$3.2M
Federal Obligation
$0.0
Non-Federal Obligation
$3.2M
Total Obligated
Activity Timeline
Subgrant Awards
Disclosed subgrants for R01AI168165
Transaction History
Modifications to R01AI168165
Additional Detail
Award ID FAIN
R01AI168165
SAI Number
R01AI168165-4174313857
Award ID URI
SAI UNAVAILABLE
Awardee Classifications
Public/State Controlled Institution Of Higher Education
Awarding Office
75NM00 NIH National Institute of Allergy and Infectious Diseases
Funding Office
75NM00 NIH National Institute of Allergy and Infectious Diseases
Awardee UEI
ED44Y3W6P7B9
Awardee CAGE
0LJH3
Performance District
AZ-07
Senators
Kyrsten Sinema
Mark Kelly
Mark Kelly
Budget Funding
| Federal Account | Budget Subfunction | Object Class | Total | Percentage |
|---|---|---|---|---|
| National Institute of Allergy and Infectious Diseases, National Institutes of Health, Health and Human Services (075-0885) | Health research and training | Grants, subsidies, and contributions (41.0) | $1,282,776 | 100% |
Modified: 6/5/26