Inhibition of Resistant Variants of HIV Protease HIV/AIDS is a serious pandemic with over 36 million infected people. Antiviral drug therapy has decreased the mortality, although the number of new infections remains about 2 million per year. However, the genetic diversity and high mutability of HIV pose a critical challenge for continued efficacy of drugs and development of effective vaccines. Hence, there is urgent need for new therapies to overcome the problem of drug-resistance. We are tackling this challenge by studying the important drug target of HIV protease. Clinical resistance arises even for the potent antiviral inhibitor darunavir. Our structural analyses have identified distinct molecular mechanisms for resistance including mutations that: 1) decrease protease interactions with inhibitors; 2) decrease the enzyme stability; or 3) influence the dynamics. In the last project period, our X-ray structures have guided the design of novel inhibitors 10-fold more effective than darunavir against highly resistant proteases. We have developed algorithms to predict resistance from genotype sequences and have identified representative mutants with high level resistance. We propose to identify common mechanism for resistance and apply these insights to design and assess new inhibitors. These multidisciplinary studies leverage the expertise, unique resources and novel approaches developed in the PIs groups together with an established set of collaborators to integrate computational, X-ray crystallographic, biochemical and biophysical techniques with inhibitor design, chemical synthesis, and virology studies. The expected outcomes will be 1) accurate predictions for resistance, 2) discovery of novel and conserved molecular mechanisms for resistance, and 3) new antiviral inhibitors for resistant HIV infections.

Public Health Relevance

A major challenge limiting success of HIV/AIDS therapy is the rapid development of viral strains with resistance to drugs. Knowledge of the relationships between sequence, structure and activities of HIV protease variants with drug resistant mutations will be applied to predict resistance and develop new antiviral agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project--Cooperative Agreements (U01)
Project #
2U01GM062920-19
Application #
9407610
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Barski, Oleg
Project Start
1997-07-01
Project End
2021-06-30
Budget Start
2017-09-20
Budget End
2018-06-30
Support Year
19
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Georgia State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Ghosh, Arun K; Brindisi, Margherita; Nyalapatla, Prasanth R et al. (2017) Design of novel HIV-1 protease inhibitors incorporating isophthalamide-derived P2-P3 ligands: Synthesis, biological evaluation and X-ray structural studies of inhibitor-HIV-1 protease complex. Bioorg Med Chem 25:5114-5127
Weber, Irene T; Harrison, Robert W (2017) Decoding HIV resistance: from genotype to therapy. Future Med Chem 9:1529-1538
Gerlits, Oksana; Keen, David A; Blakeley, Matthew P et al. (2017) Room Temperature Neutron Crystallography of Drug Resistant HIV-1 Protease Uncovers Limitations of X-ray Structural Analysis at 100 K. J Med Chem 60:2018-2025
Ghosh, Arun K; Sean Fyvie, W; Brindisi, Margherita et al. (2017) Design, synthesis, X-ray studies, and biological evaluation of novel macrocyclic HIV-1 protease inhibitors involving the P1'-P2' ligands. Bioorg Med Chem Lett 27:4925-4931
Ghosh, Arun K; Rao, Kalapala Venkateswara; Nyalapatla, Prasanth R et al. (2017) Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants. J Med Chem 60:4267-4278
Ghosh, Arun K; Osswald, Heather L; Glauninger, Kristof et al. (2016) Probing Lipophilic Adamantyl Group as the P1-Ligand for HIV-1 Protease Inhibitors: Design, Synthesis, Protein X-ray Structural Studies, and Biological Evaluation. J Med Chem 59:6826-37
Gerlits, Oksana; Wymore, Troy; Das, Amit et al. (2016) Long-Range Electrostatics-Induced Two-Proton Transfer Captured by Neutron Crystallography in an Enzyme Catalytic Site. Angew Chem Int Ed Engl 55:4924-7
Park, Joon H; Sayer, Jane M; Aniana, Annie et al. (2016) Binding of Clinical Inhibitors to a Model Precursor of a Rationally Selected Multidrug Resistant HIV-1 Protease Is Significantly Weaker Than That to the Released Mature Enzyme. Biochemistry 55:2390-400
Weber, Irene T; Harrison, Robert W (2016) Tackling the problem of HIV drug resistance. Postepy Biochem 62:273-279
Shen, ChenHsiang; Yu, Xiaxia; Harrison, Robert W et al. (2016) Automated prediction of HIV drug resistance from genotype data. BMC Bioinformatics 17 Suppl 8:278

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