Related Experiment Video
Updated: Oct 30, 2025
Author Spotlight: Exploring Cytoskeletal Dynamics to Unveil Novel Antibiotics Through Innovative Cell-Based Assays
Published on: April 26, 2024
Single-Agent and Fixed-Dose Combination HIV-1 Protease Inhibitor Drugs in Fission Yeast (Schizosaccharomyces pombe)
Jiantao Zhang1, Kasey Vernon1, Qi Li1
1Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Abstract:
Successful combination antiretroviral therapies (cART) eliminate active replicating HIV-1, slow down disease progression, and prolong lives. However, cART effectiveness could be compromised by the emergence of viral multidrug resistance, suggesting the need for new drug discoveries. The objective of this study was to further demonstrate the utility of the fission yeast cell-based systems that we developed previously for the discovery and testing of HIV protease (PR) inhibitors (PIs) against wild-type or multi-PI drug resistant M11PR that we isolated from an infected individual. All thirteen FDA-approved single-agent and fixed-dose combination HIV PI drugs were tested. The effect of these drugs on HIV PR activities was tested in pure compounds or formulation drugs. All FDA-approved PI drugs, except for a prodrug FPV, were able to suppress the wild-type PR-induced cellular and enzymatic activities. Relative drug potencies measured by EC50 in fission yeast were discussed in comparison with those measured in human cells. In contrast, none of the FDA-approved drugs suppressed the multi-PI drug resistant M11PR activities. Results of this study show that fission yeast is a reliable cell-based system for the discovery and testing of HIV PIs and further demonstrate the need for new PI drugs against viral multi-PI resistance.
Insights
New HIV protease inhibitors are needed as current drugs fail against resistant strains. Fission yeast systems effectively test drug efficacy, highlighting the urgent need for novel treatments against multidrug-resistant HIV.
Area of Science:
- Virology
- Drug Discovery
- Microbiology
Background:
- Combination antiretroviral therapies (cART) are vital for managing HIV-1, but drug resistance limits their long-term effectiveness.
- Emergence of multidrug-resistant HIV strains necessitates the development of novel therapeutic agents.
- Existing HIV protease inhibitors (PIs) may become ineffective against resistant viral variants.
Purpose of the Study:
- To validate a fission yeast cell-based system for discovering and evaluating HIV protease inhibitors (PIs).
- To test the efficacy of FDA-approved PIs against both wild-type and multidrug-resistant HIV protease (M11PR).
Main Methods:
- Utilized a previously developed fission yeast system to assess HIV protease activity.
- Tested thirteen FDA-approved single-agent and fixed-dose combination HIV PI drugs against wild-type and M11PR.
- Measured drug potencies (EC50) in fission yeast and compared them to human cell data.
Main Results:
- All tested FDA-approved PIs, except FPV, suppressed wild-type HIV protease activity in the yeast system.
- No FDA-approved PIs demonstrated efficacy against the multidrug-resistant M11PR.
- Fission yeast proved to be a reliable platform for evaluating PI effectiveness.
Conclusions:
- The fission yeast system is a viable tool for HIV PI discovery and testing.
- Current FDA-approved PIs are ineffective against the tested multidrug-resistant HIV strain.
- There is a critical need for new PIs to overcome existing viral multidrug resistance.
