Graduate School of Biomedical Sciences, Biochemistry and Molecular Pharmacology
Dissertations, UMMS; Drug Resistance, Viral; HIV Protease; HIV Protease Inhibitors; Hepacivirus; Viral Nonstructural Proteins
Immunology and Infectious Disease | Molecular Biology | Structural Biology | Virology
Drug resistance is a major problem in quickly evolving diseases, including the human immunodeficiency (HIV) and hepatitis C viral (HCV) infections. The viral proteases (HIV protease and HCV NS3/4A protease) are primary drug targets. At the molecular level, drug resistance reflects a subtle change in the balance of molecular recognition; the drug resistant protease variants are no longer effectively inhibited by the competitive drug molecules but can process the natural substrates with enough efficiency for viral survival. Therefore, the inhibitors that better mimic the natural substrate binding features should result in more robust inhibitors with flat drug resistance profiles. The native substrates adopt a consensus volume when bound to the enzyme, the substrate envelope. The most severe resistance mutations occur at protease residues that are contacted by the inhibitors outside the substrate envelope. To guide the design of robust inhibitors, we investigate the shared and varied properties of substrates with the protein dynamics taken into account to define the dynamic substrate envelope of both viral proteases. The NS3/4A dynamic substrate envelope is compared with inhibitors to detect the structural and dynamic basis of resistance mutation patterns. Comparative analyses of substrates and inhibitors result in a solid list of structural and dynamic features of substrates that are not shared by inhibitors. This study can help guiding the development of novel inhibitors by paying attention to the subtle differences between the binding properties of substrates versus inhibitors.
Ozen, Aysegul, "Structure and Dynamics of Viral Substrate Recognition and Drug Resistance: A Dissertation" (2013). University of Massachusetts Medical School. GSBS Dissertations and Theses. Paper 677.
Available for download on Thursday, January 01, 2015