Project 1: Structural Analysis of HIV Entry Inhibition Our overall objective is to provide an atomic-level understanding of opportunities for intervention in processes of cell entry by HIV. We plan to continue our structural studies on HIV gpl20 in the context of this program project on antagonism of HIV envelope function in cell entry. Our technical focus is on x-ray crystallography, so as to determine structures at sufficient resolution to develop mechanistic insights, but associated binding experiments and computations will also be performed.
Our aims i nclude using crystal structure to screen for new lead compounds, structural analyses of complexes of HIV gp120 with candidate inhibitory molecules, structural studies of HIV gpl20 interactions with other natural binding partners besides CD4, and innovative computational analyses of gp 120 plasticity. We build not only on our recent experience in this project, but also on our earlier structural investigations of CD4, HIV gp120s, and associated antibodies. We have adopted or developed both appropriate expression systems for making the required proteins and also appropriate assays for following inhibitory action. We interact with all other elements of the program project: most intimately with Project 3 on chemistry (Smith) and Project 5 on virology (Sodroski), but also significantly with Project 2 on peptidomimetics and miniproteins (Chaiken), Project 4 on thermodynamics (Freire), prospectively with Project 6 on dynamics by single-molecule FRET (Mothes), and importantly with the computation core (LaLonde).
|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:|
|Johnson, Jacklyn; Zhai, Yinjie; Salimi, Hamid et al. (2017) Induction of a Tier-1-Like Phenotype in Diverse Tier-2 Isolates by Agents That Guide HIV-1 Env to Perturbation-Sensitive, Nonnative States. J Virol 91:|
|Herschhorn, Alon; Sodroski, Joseph (2017) An entry-competent intermediate state of the HIV-1 envelope glycoproteins. Receptors Clin Investig 4:|
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