Abstract

The objective of this project is to establish a Crystallography Core to produce accurate three-dimensional models relevant to the program of projects in Structure-Based CD4-gp120 Antagonism. This core will interact with all other components of the program and, in particular, will participate in the design of antagonists based on the crystallographic structures of relevant complexes. Thereby, the Crystallography Core will contribute to the effort to design therapeutics suitable for the management or prevention of AIDS.
The specific aims of this scientific core are: (1) to analyze complexes of candidate small molecules with HIV-1 gp120, (2) to analyze complexes of candidate miniproteins with HIV-1 gp10, (3) to analyze complexes of the CD4 D1D2 fragment with drug- resistant gp120 variants, (4) to analyze other relevant complexes that might be developed, such as with D1D2, sCD4 or fragments of chemokine receptors, and (5) to design or improve upon compounds that will inhibit the CD4-gp120 interaction.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM056550-05
Application #
6474617
Study Section
Project Start
2001-08-01
Project End
2002-07-31
Budget Start
Budget End
Support Year
5
Fiscal Year
2001
Total Cost
$157,210
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

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:
Pacheco, Beatriz; Alsahafi, Nirmin; Debbeche, Olfa et al. (2017) Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors. J Virol 91:
Rashad, Adel A; Acharya, Kriti; Haftl, Ann et al. (2017) Chemical optimization of macrocyclic HIV-1 inactivators for improving potency and increasing the structural diversity at the triazole ring. Org Biomol Chem 15:7770-7782

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