B.A., Physics, Cambridge University, Cambridge, UK 1974
M.A., Physics, Cambridge University, Cambridge, UK, 1978
D. Phil., Molecular Biophysics, Oxford University, Oxford, UK, 1978
Postdoc, Yale University, 1978-1984
Research Associate, National Bureau of Standards, 1985-1987
Staff Scientist, NCI-Frederick Cancer Research Facility, 1987-1991
Molecular Genetics and Biochemistry Research Group, Neurobiology and Behavior Research Group, Molecular Genetics/Cell Physiology, Structural Biochemistry and Bioinformatics
My research focuses on understanding the structures and mechanisms of key proteins, structure-guided design of inhibitors for drug resistant HIV/AIDS and bacterial infections, and the molecular basis for chronic diseases. These studies benefit from local, national and international collaborations. Our long-term studies of HIV protease address the critical medical challenge of drug resistance in the HIV/AIDS pandemic by analyzing the crystal structures and activities of drug resistant protease variants, and thereby guiding the design of new antiviral inhibitors. We were the first to report the crystal structure of HIV protease in complex with the potent antiviral inhibitor darunavir, which has proved highly effective in treating resistant HIV/AIDS. We are developing and validating machine learning methods to predict drug resistance from genotype/phenotype data. Our studies have elucidated multiple molecular mechanisms for resistance to protease inhibitors. Individual mutations can act by altering the interaction with clinical inhibitors or by altering the dimer interface or stability of the enzyme. We have characterized the unique properties of highly resistant protease variants with drastically lower susceptibility for clinical inhibitors. This analysis of drug resistant mutants gives insight into the most effective designs for new inhibitors to combat resistant HIV infections. In addition, we study the structures and mechanisms of various bacterial enzymes as well as proteins implicated in cancer and diabetes.
Agniswamy J, Louis JM, Roche J, Harrison RW, Weber IT. (2016) Structural studies of a rationally selected multi-drug resistant HIV-1 protease reveal synergistic effect of distal mutations on flap dynamics. Plos One, 11(12):e0168616.
Weber IT, Harrison RW. (2017) Decoding HIV Resistance: From Genotype to Therapy. Fut. Med. Chem. 9, 1529-1538.
Sachla AJ, Ouattara M, Romero E, Agniswamy J, Weber IT, Gadda G, Eichenbaum Z. In vitro heme biotransformation by the HupZ enzyme from Group A streptococcus. (2016) Biometals. 29, 593-609.
Ghosh AK, Rao KV, Nyalapatla PR, Osswald HL, Martyr CD, Aoki M, Takayama J, Hayashi H,, Agniswamy J, Wang YF, Bulut H, Das D, Weber, IT, Mitsuya M. Design and Development of Highly Potent HIV1 Protease Inhibitors with a Crownlike Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants. (2017) J. Med. Chem 60, 4267-4278.