The HIV-1 envelope glycoprotein gp120 plays a critical role in mediating viral entry into host cells and has been validated as a prime target for small-molecule drugs and vaccine development, yet no drugs against gp120 have been approved by the US Food and Drug Administration (FDA) to date. Therefore, there is a critical need to develop novel drugs against this target. Our group made significant headway in filling this critical need by developing a new class of HIV-1 entry inhibitors targeted to the Phe43 cavity of HIV-1 gp120. This renewal application builds on the in-depth knowledge gained during the current funding cycle from the extensive X-ray structure, synthesis, as well as the antiviral activity and toxicity data and in vitro ADMET profiles of this class of novel entry inhibitor. The development of novel therapeutics will aid in increasing the number of new and novel drugs available, especially for the treatment-experienced patients, who have limited treatment options and will extend the scope of combination therapy. This highly coordinated effort will further our goal of developing potent inhibitors for moving to the next phase of preclinical assessments in animals and for selecting two to three inhibitors as potential clinical candidates. Our long-term goal is to develop novel, highly potent, and less toxic oral anti-HIV drugs, which are expected to serve as a new arsenal for combination therapy, especially for treatment-experienced patients. We will achieve our goals by addressing four highly coordinated, hypothesis-driven specific aims: 1. Optimize next-generation HIV-1 entry antagonists by structure- based design and comprehensive medicinal chemistry. 2. Evaluate the antiviral potency, toxicity, mechanism of action, and drug resistance. 3. Measure the binding thermodynamics and determine the X-ray structure of the most potent entry inhibitors with (a) monomeric gp120 and (b) trimeric gp120. 4. Evaluate the in vitro ADMET and in vivo pharmacokinetics (PK) in laboratory animals.
(Public Health Relevance Statement) The goal of this proposal is to optimize the lead HIV-1 entry antagonists targeted to the CD4 binding site of gp120 that have the potential to escape resistance and become clinically relevant and potent entry inhibitors. These next generation entry inhibitors are expected to expand the arsenal of drugs for AIDS therapy and prevention.
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|Curreli, Francesca; Belov, Dmitry S; Ramesh, Ranjith R et al. (2016) Design, synthesis and evaluation of small molecule CD4-mimics as entry inhibitors possessing broad spectrum anti-HIV-1 activity. Bioorg Med Chem 24:5988-6003|
|Lu, Lu; Yu, Fei; Cai, Lifeng et al. (2016) Development of Small-molecule HIV Entry Inhibitors Specifically Targeting gp120 or gp41. Curr Top Med Chem 16:1074-90|
|Curreli, Francesca; Haque, Kashfia; Xie, Lihua et al. (2015) Synthesis, antiviral activity and resistance of a novel small molecule HIV-1 entry inhibitor. Bioorg Med Chem 23:7618-28|
|Curreli, Francesca; Kwon, Young Do; Zhang, Hongtao et al. (2015) Structure-Based Design of a Small Molecule CD4-Antagonist with Broad Spectrum Anti-HIV-1 Activity. J Med Chem 58:6909-6927|
|Curreli, Francesca; Kwon, Young Do; Zhang, Hongtao et al. (2014) Binding mode characterization of NBD series CD4-mimetic HIV-1 entry inhibitors by X-ray structure and resistance study. Antimicrob Agents Chemother 58:5478-91|