The central objective of this Project is to use the structures of the gp120/CD3=4 complex and of D1-D4 CD4 to identify topographical regions of these proteins which when transplanted into miniproteins or mimicked in peptides and small molecules will generate new ligands with which to antagonise the interaction of human cells with HIV-1, the human immunodeficiency virus responsible for AIDS. T-cell docking and entry by HIV-1, a major route of cell infiltration and resultant infection in AIDS, is driven by specific recognition of the T-cell surface protein CD4 with the HIV envelope protein gp120. The crystallographic structure of CD4 is known, and that of its complex with gp120 is closed at hand. Structural components in both protein partners have been identified which are proposed to play key roles in CD4- gp120 recognition. The advancing high resolution structural understanding of the protein participants in virus-cell recognition together with the advancing technology of mimetics design now make it possible to combine structure determination, modeling, miniprotein engineering and organic synthesis to design new antagonists for AIDS.
The specific aims of this proposal are: (1) Identify binding sites in the CD4/gp120 interface by computational modeling of existing high resolution structures; and (2) Utilize key structural elements as determined from high resolution structure; modeling and miniprotein, constrained peptide and nonpeptide scaffolds to design small molecule CD4 antagonists for AIDS. The ultimate goal of this grant proposal is to produce a small molecule capable of antagonizing the interaction of CD4 and gp120.
|Castillo-Menendez, Luis R; Witt, Kristen; Espy, Nicole et al. (2018) Comparison of Uncleaved and Mature Human Immunodeficiency Virus Membrane Envelope Glycoprotein Trimers. J Virol 92:|
|Rashad, Adel A; Song, Li-Rui; Holmes, Andrew P et al. (2018) Bifunctional Chimera That Coordinately Targets Human Immunodeficiency Virus 1 Envelope gp120 and the Host-Cell CCR5 Coreceptor at the Virus-Cell Interface. J Med Chem 61:5020-5033|
|Moraca, Francesca; Rinaldo, David; Smith 3rd, Amos B et al. (2018) Specific Noncovalent Interactions Determine Optimal Structure of a Buried Ligand Moiety: QM/MM and Pure QM Modeling of Complexes of the Small-Molecule CD4 Mimetics and HIV-1 gp120. ChemMedChem 13:627-633|
|Castillo-Menendez, Luis R; Nguyen, Hanh T; Sodroski, Joseph (2018) Conformational Differences Between Functional Human Immunodeficiency Virus (HIV-1) Envelope Glycoprotein Trimers and Stabilized Soluble Trimers. J Virol :|
|Madani, Navid; Princiotto, Amy M; Mach, Linh et al. (2018) A CD4-mimetic compound enhances vaccine efficacy against stringent immunodeficiency virus challenge. Nat Commun 9:2363|
|Kisalu, Neville K; Idris, Azza H; Weidle, Connor et al. (2018) A human monoclonal antibody prevents malaria infection by targeting a new site of vulnerability on the parasite. Nat Med 24:408-416|
|Parajuli, Bibek; Acharya, Kriti; Bach, Harry C et al. (2018) Restricted HIV-1 Env glycan engagement by lectin-reengineered DAVEI protein chimera is sufficient for lytic inactivation of the virus. Biochem J 475:931-957|
|Ma, Xiaochu; Lu, Maolin; Gorman, Jason et al. (2018) HIV-1 Env trimer opens through an asymmetric intermediate in which individual protomers adopt distinct conformations. Elife 7:|
|Witt, Kristen C; Castillo-Menendez, Luis; Ding, Haitao et al. (2017) Antigenic characterization of the human immunodeficiency virus (HIV-1) envelope glycoprotein precursor incorporated into nanodiscs. PLoS One 12:e0170672|
|Go, Eden P; Ding, Haitao; Zhang, Shijian et al. (2017) Glycosylation Benchmark Profile for HIV-1 Envelope Glycoprotein Production Based on Eleven Env Trimers. J Virol 91:|
Showing the most recent 10 out of 146 publications