Organic synthesis and enzymatic assays Core 1 - Ali, UMASS Medical School Drug resistance is a major limitation in the treatment of many pathogenic infections and cancers. Understanding the mechanisms of drug resistance and developing strategies to avoid resistance could lead to more effective treatments. Due to the plethora of available data, HIV-1 protease is a unique model system to study the mechanisms of drug resistance. In this highly interdisciplinary Program Project, we aim to elucidate the molecular mechanisms of drug resistance in HIV-1 protease and develop drug design strategies to avoid resistance. The Core 1 will provide medicinal chemistry support to the members of the Program Project. We will synthesize protease inhibitors and analogues required for co-crystallization, ITC, NMR, and resistance selection studies. We will work closely with the computational and structural biology groups to design new inhibitors using multiple core scaffolds that fully leverage the interdependence of different sub-sites in HIV-1 protease recognition. We will carry out the chemical synthesis of designed inhibitors and evaluate their activities in enzymatic assays against wild-type protease and drug-resistant variants. This highly collaborative and integrated approach will help elucidate the mechanisms of drug resistance and provide strategies to design more robust inhibitors less susceptible to drug resistance.
Organic synthesis and enzymatic assays Core 1 - Ali, UMASS Medical School HIV-1 protease inhibitors are the most potent antiretroviral drugs for the treatment of HIV infection, but their efficacy is limited due to the rapid acquisition of drug resistance. HIV-1 protease provides a unique opportunity to understand the molecular mechanisms of drug resistance and develop strategies for avoiding drug resistance. The Core 1 will provide medicinal chemistry support to the members of the Program Project, work closely with Project 3 and synthesize protease inhibitors and analogues required for the experimental studies in Projects 1 and 2.
|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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