The structural &dynamic basis for the interdependence of drug resistance Project 1 - Schiffer, UMASS Medical School In many drug resistance variants variants, multiple site mutations co-evolve to both decrease the affinity of a particular inhibitor and increase the viability and fitness of the enzyme. We hypothesize that the impact of particular mutations on conferring drug resistance is not simply additive, but that these mutations have a complex interdependent effect leading to viable variants that are highly resistant to existing drugs. As a project team we will test this hypothesis through a systematic and quantitative evaluation of the interdependency in drug resistance at the molecular level in HIV protease, through changes in the protease structure, thermodynamics, enzyme kinetics and dynamics by state-of-the-art experimental and computational techniques and apply this knowledge to develop inhibitors with high barrier to resistance. This data will identify residues and combinations of mutations that are pivotal signature sites in conferring drug resistance. Such a strategy is critical to revealing the complex molecular mechanisms of drug resistance, and both avoid resistance from the start and target highly resistant variants seen in clinic. This strategy will be directly applicable to other quickly evolving diseases where drug resistance thwarts effective therapy.

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The structural &dynamic basis for the interdependence of drug resistance Project 1 - Schiffer, UMASS Medical School Drug resistance involves complex changes in the structure and dynamics of the therapeutic target. Studying HIV protease and using biophysical and structural biology techniques we are elucidating the molecular mechanisms of drug resistance should lead to strategies of avoiding drug resistance.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Leidner, Florian; Kurt Yilmaz, Nese; Paulsen, Janet et al. (2018) Hydration Structure and Dynamics of Inhibitor-Bound HIV-1 Protease. J Chem Theory Comput 14:2784-2796
Nemmara, Venkatesh V; Subramanian, Venkataraman; Muth, Aaron et al. (2018) The Development of Benzimidazole-Based Clickable Probes for the Efficient Labeling of Cellular Protein Arginine Deiminases (PADs). ACS Chem Biol 13:712-722
Ilina, Tatiana V; Slack, Ryan L; Elder, John H et al. (2018) Effect of tRNA on the Maturation of HIV-1 Reverse Transcriptase. J Mol Biol 430:1891-1900
Khan, Shahid N; Persons, John D; Paulsen, Janet L et al. (2018) Probing Structural Changes among Analogous Inhibitor-Bound Forms of HIV-1 Protease and a Drug-Resistant Mutant in Solution by Nuclear Magnetic Resonance. Biochemistry 57:1652-1662
Persons, John D; Khan, Shahid N; Ishima, Rieko (2018) An NMR strategy to detect conformational differences in a protein complexed with highly analogous inhibitors in solution. Methods 148:9-18
Potempa, Marc; Lee, Sook-Kyung; Kurt Yilmaz, Nese et al. (2018) HIV-1 Protease Uses Bi-Specific S2/S2' Subsites to Optimize Cleavage of Two Classes of Target Sites. J Mol Biol 430:5182-5195
Tilvawala, Ronak; Nguyen, Son Hong; Maurais, Aaron J et al. (2018) The Rheumatoid Arthritis-Associated Citrullinome. Cell Chem Biol 25:691-704.e6
Venev, Sergey V; Zeldovich, Konstantin B (2018) Thermophilic Adaptation in Prokaryotes Is Constrained by Metabolic Costs of Proteostasis. Mol Biol Evol 35:211-224
Wong, Alicia; Bryzek, Danuta; Dobosz, Ewelina et al. (2018) A Novel Biological Role for Peptidyl-Arginine Deiminases: Citrullination of Cathelicidin LL-37 Controls the Immunostimulatory Potential of Cell-Free DNA. J Immunol 200:2327-2340
Sun, Bo; Dwivedi, Nishant; Bechtel, Tyler J et al. (2017) Citrullination of NF-?B p65 promotes its nuclear localization and TLR-induced expression of IL-1? and TNF?. Sci Immunol 2:

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