There is an urgent need for new drugs to treat HIV/AIDS, particularly the discovery and development of compounds that are active against virus isolates resistant to currently approved therapies. During my pre-academic career, we reported on 3-O-(3',3'-dimethylsuccinyl) betulinic acid (PA-457), first in a new class of HIV-1 maturation inhibitors with efficacy against strains resistant to current therapies. Unlike protease inhibitors, PA-457 blocks a single step in the processing of the viral Gag protein: protease cleavage of the Gag capsid (CA) precursor (CA-SP1) to mature CA protein. This results in the release of immature, non-infectious viral particles, and also raises several interesting questions about the mechanism of action, molecular determinants, and identity of molecular target for this novel HIV-1 inhibitor. I would like these questions along with the development of additional maturation inhibitors to be the center of my career research. I would like to establish myself as a productive scientist in retrovirus maturation, a relatively unexplored research area. Work by our group and others has demonstrated that residues within the HIV-1 Gag CA-SP1 boundary region serve as determinants of PA-457 activity, and genetic variation within this region allows HIV-1 to escape PA-457-mediated inhibition. More recent results support the theory that a direct interaction between the compound and an oligomeric form of Gag is critical to PA-457 activity. While these observations allow insight into the PA-457 antiviral effect, the mechanisms of action and resistance of PA-457 remain to be fully determined. We propose to further characterize the mechanism of action of PA-457 activity and further elucidate the molecular determinants of PA-457 activity. We believe that the results of our studies will provide greater insight into the mechanisms of action and resistance of PA-457 as well as into the precise molecular determinant of PA-457 activity. A better understanding of these issues is particularly relevant due to PA-457's ongoing clinical development (currently in Phase 2b trial). We are confident that the results of these studies will aid in the development of additional classes of HIV-1 maturation inhibitors and help elucidate the basic mechanism of HIV-1 maturation. Lay Language: Drug resistance is the leading reason for HIV treatment failure. Completion of the proposed research will help identify novel HIV maturation inhibitors, provide additional treatment options, and improve disease outcome.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Scientist Development Award - Research (K02)
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Acquired Immunodeficiency Syndrome Research Review Committee (AIDS)
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Gupta, Kailash C
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South Dakota State University
Veterinary Sciences
Schools of Earth Sciences/Natur
United States
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Wang, Dan; Lu, Wuxun; Li, Feng (2015) Pharmacological intervention of HIV-1 maturation. Acta Pharm Sin B 5:493-9
Demers, Andrew; Ran, Zhiguang; Deng, Qiji et al. (2014) Palmitoylation is required for intracellular trafficking of influenza B virus NB protein and efficient influenza B virus growth in vitro. J Gen Virol 95:1211-20
Ran, Zhiguang; Chen, Ying; Shen, Huigang et al. (2013) In vitro and in vivo replication of influenza A H1N1 WSN33 viruses with different M1 proteins. J Gen Virol 94:884-95
Deng, Qiji; Song, Minxun; Demers, Andrew et al. (2012) Biochemical characterization of the small hydrophobic protein of avian metapneumovirus. Virus Res 167:297-301
Wang, Dan; Wise, Mitchell L; Li, Feng et al. (2012) Phytochemicals attenuating aberrant activation of β-catenin in cancer cells. PLoS One 7:e50508
Lu, Wuxun; Salzwedel, Karl; Wang, Dan et al. (2011) A single polymorphism in HIV-1 subtype C SP1 is sufficient to confer natural resistance to the maturation inhibitor bevirimat. Antimicrob Agents Chemother 55:3324-9
Deng, Qiji; Wang, Dan; Xiang, Xiaoxiao et al. (2011) Nuclear localization of influenza B polymerase proteins and their binary complexes. Virus Res 156:49-53
Wang, Dan; Harmon, Aaron; Jin, Jing et al. (2010) The lack of an inherent membrane targeting signal is responsible for the failure of the matrix (M1) protein of influenza A virus to bud into virus-like particles. J Virol 84:4673-81