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
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Wong-Sam, Andres; Wang, Yuan-Fang; Zhang, Ying et al. (2018) Drug Resistance Mutation L76V Alters Nonpolar Interactions at the Flap-Core Interface of HIV-1 Protease. ACS Omega 3:12132-12140
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Ghosh, Arun K; Jadhav, Ravindra D; Simpson, Hannah et al. (2018) Design, synthesis, and X-ray studies of potent HIV-1 protease inhibitors incorporating aminothiochromane and aminotetrahydronaphthalene carboxamide derivatives as the P2 ligands. Eur J Med Chem 160:171-182
Ghosh, Arun K; Rao, Kalapala Venkateswara; Nyalapatla, Prasanth R et al. (2018) Design of Highly Potent, Dual-Acting and Central-Nervous-System-Penetrating HIV-1 Protease Inhibitors with Excellent Potency against Multidrug-Resistant HIV-1 Variants. ChemMedChem 13:803-815
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Ghosh, Arun K; Fyvie, W Sean; Brindisi, Margherita et al. (2017) Design, Synthesis, Biological Evaluation, and X-ray Studies of HIV-1 Protease Inhibitors with Modified P2' Ligands of Darunavir. ChemMedChem 12:1942-1952
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; 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

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