SUMMARY:
UCLA researchers in the Department of Neurology have developed a novel small-molecule protease inhibitor cocktail to robustly suppress COVID-19 infection.
INTRODUCTION:
COVID-19 is an infectious disease caused by the SARS-CoV-2 virus. Despite the development of vaccines, COVID-19 was the third-leading cause of death in the U.S. in 2021, highlighting the continued need for more and varied interventions against the disease, especially for immunocompromised individuals. The urgency for further development of effective interventions is further stressed by the anticipated rise of more variants. One strategy being explored in the development of antiviral medications to mitigate severe COVID-19 infections is targeting of the virus’s two cysteine proteases, the main protease (Mpro) and the papain-like protease (PLpro), that mediate host immune response evasion and viral replication. These proteases are promising drug targets since they are dissimilar to human proteases and crucial to infection. Most research has so far focused on developing inhibitors for Mpro, and clinical data has shown that they successfully reduce hospitalization from COVID-19. Clinical effectiveness of protease inhibitor cocktails for treatment against HIV and Hepatitis C support the potential of using protease drug combinations for effective healthcare management and treatment of COVID-19. Thus, there is great potential that PLpro-targeting drugs, in combination with Mpro protease inhibitors, could further improve suppression of COVID-19 infections and reduce mortality. This approach would also decrease the likelihood of emergence of viral drug resistant mutants as it would be much harder for the virus to out-mutate two inhibitors at the same time.
INNOVATION
UCLA researchers led by Professor Varghese John, Director of the Drug Discovery Lab in the Department of Neurology, in collaboration with Professor Robert Damoiseaux in the Department of Molecular and Medical Pharmacology and Director of the Molecular Screening Platform at the Californina NanoSystems Institute, along with Professor Melody Li a UCLA virologist, have identified a FDA approved drug that functions as a PLpro protease inhibitor and could be used to treat COVID-19. The research team employed high-throughput screening using a clinical compound library to identify molecules that inhibit PLpro. The drug is known to inhibit viral replication in Vero cells infected with SARS-CoV-2, the researchers tested the drug’s dose-response against inhibition of PLpro, its deubiquitinase and interferon-stimulated gene product activity. They found that the IC50 of the compound for PLpro inhibition is lower than its steady state plasma levels achieved clinically, after administration of a typically used dosage. This indicates that the current FDA approved dosage of the drug would inhibit the PLpro enzyme in patients and should produce robust suppression of COVID-19 infection. The researchers also demonstrated that the drug can work as a PLpro inhibitor in combination with the Mpro inhibitor nirmatrelvir and paxlovid. Thus the drug when administered in combination with existing, clinically used Mpro inhibitors should show robust antiviral activity against SARS-CoV-2. Taken together, repurposing of this already FDA-approved drug in protease cocktails could be used to treat severe COVID-19 cases and reduce hospitalization and deaths resulting from the disease, and speed up post-infection recovery. This drug combination is also likely to more resistant to emergence of single agent resistant viral mutants.
POTENTIAL APPLICATIONS:
- Antiviral medication used by itself or in combination as a protease cocktail for more effective COVID-19 treatment, particularly for patients with high risk factors
ADVANTAGES:
- Drug is already available as an oral tablet for easy administration.
- FDA-approved dosages of the drug achieve plasma levels that are above its IC50 for inhibiting PLpro, so clinical approval can be expedited
- Fewer anticipated COVID-19 long term side effects due to the uniqueness of PLpro to SARS-CoV-2
- Resistance to the development of single agent resistant viral mutants
DEVELOPMENT-TO-DATE:
- The researchers have established that the candidate drug effectively inhibits PLpro enzyme, by itself and in combination with MPro inhibitors and clinically the protease cocktail could be highly effective against SARS-CoV-2.
- Based on their findings, the researchers have designed novel drug candidates with greater binding affinity to the active site domain of PLpro, and are working on synthesizing these compounds.
RELEVANT PUBLICATIONS:
Identification of a Papain-Like Protease Inhibitor with Potential for Repurposing in Combination with an Mpro Protease Inhibitor for Treatment of SARS-CoV-2
Jesus Campagna, Barbara Jagodzinska, Pablo Alvarez, Constance Yeun, Patricia Spilman, Kathryn M. Enquist, Whitaker Cohn, Pavla Fajtová, Anthony J. O’Donoghue, Vaithilingaraja Arumugaswami, Melody M.H. Li, Robert Damoiseaux, Varghese John
bioRxiv 2022.07.18.500363; doi: https://doi.org/10.1101/2022.07.18.500363