The entry of HIV-1 into host cells is mediated by the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. The structures of the gp120-CD4-17b complex indicate that the CD4 binding site (CD4BS) on gp120 is located in a hydrophobic cavity, termed """"""""Phe43 cavity"""""""" where Phe43CD4 makes critical hydrophobic contacts. Studies of these structures also confirmed an important electrostatic interaction between Arg59CD4 and Asp368gp120. Similar structural mimicry of several potent broad neutralizing antibodies (bNAbs) has recently been reported. The highly conserved nature of the residues in the CD4BS of gp120 and their role in binding to CD4 and CD4BS targeted bNAbs validates this site as a promising target for therapeutic and prophylactic intervention. Despite th remarkable diversity of the HIV-1 envelope glycoprotein sequence, glycosylation and conformational flexibility, gp120 must retain conserved domains required for binding to CD4. However, the well-conserved CD4 binding site has yet to be exploited to its full potential as a target in designing drugs to prevent HIV-1 entry, which will be the focus of our research. We were the first to identify two small molecule inhibitors, NBD-556 and NBD-557, which target the CD4BS on gp120. These molecules show unprecedented ability to induce conformational changes in gp120 similar to that of CD4;thereby, acting as agonists. Recently, we solved the structure of NBD-556 in complex with the gp120 coree, confirming that NBD-556 binds to the cavity of gp120. We used this structure to design new leads with improved anti-HIV-1 activity. However, these lead compounds showed CD4 agonist properties. In additional studies, we confirmed that a newly designed lead, NBD-11021, is a CD4 antagonist. Moreover, a recent report showed that the bNAb PGV04 targets the CD4BS but induces distinct conformational changes in gp120 that are not recognized by the 17b antibody. PGV04 thus does not induce exposure of the coreceptor binding site, suggesting that it is a CD4 antagonist not an agonist. We hypothesize that lead compounds, including NBD-11021, can be optimized by incorporating the distinct binding features of PGV04 with gp120 to produce a more potent and selective new class of HIV-1 entry inhibitors with CD4 antagonist properties. The goals of the proposed studies will be accomplished by three highly integrated specific aims.
In Aim -1, the leads will be optimized through structure-guided design and medicinal chemistry.
In Aim -2, thermodynamic and kinetic properties such as enthalpy, entropy, on- and off-rates and binding affinity (KD) will be measured as well as their antiviral potency and toxicity. The x-ray structures of new inhibitors in complex with gp120 will be determined.
In Aim -3, mechanism of action will be studied and the resistant mutants of the inhibitors will be selected. The data from these studies will be used in designing potent next-generation entry inhibitors that will potentially escape resistance and be clinically relevant. The long-term goal is to develop a new class of HIV-1 entry inhibitors for pre clinical and clinical studies.
The first step in HIV-1 infection is the entry of the virus to the host cell. The goal of this proposal is to design novel HIV-1 inhibitors that prevent virus from entering the host cells. These next generation entry inhibitors will help to expand the arsenal of drugs for AIDS therapy and prevention as microbicides.
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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|
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|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|