The Principal Aim of Core A will be to support the Overarching Goal of this Program Project to identify small molecule and peptide Env gp120 inhibitors, defining their structural mechanisms of action by exploiting structure-mechanism correlations as a guide to optimize antagonist function. To this end, Core A will focus on the recent significant progress made by the Program Project in the development of small molecule and peptidomimetic viral entry antagonists, in conjunction with the emerging structural information of both gpl20 monomer and the Env trimer. We will focus on three Env interfaces that mediate HIV-1 infection. These are: (A) the highly conserved CD4-gp120 binding site;(B) the chemokine receptor-gp120 V3-loop interface;and (C) the gp41-interacfing element of gpl20. During the recent grant period Core A successfully guided cycles of design, synthesis and structure determination for gp 120 antagonists. Building on this success, we will continue to integrate with Crystallography (Hendrickson and Kwong), Virology (Sodroski), Peptide and Mini-proteins (Chaiken), Small Molecule Synthesis (Smith), Thermodynamics (Freire), and Single Molecule FRET (Mothes and Blanchard). Antagonists (peptides, small molecules and fragments) discovered and validated by these groups, will in turn be optimized computationally by Core A, and in collaboration with the Synthetic (Smith) and Peptide/Peptidomimetic Projects (Chaiken) advance novel small molecules and peptides for virological testing and validation (Sodroski).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
5P01GM056550-18
Application #
8740493
Study Section
Special Emphasis Panel (ZRG1-AARR-E)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
18
Fiscal Year
2014
Total Cost
$101,771
Indirect Cost
$30,985
Name
Drexel University
Department
Type
DUNS #
002604817
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Clarkson, Benjamin R; Schön, Arne; Freire, Ernesto (2016) Conformational stability and self-association equilibrium in biologics. Drug Discov Today 21:342-7
Moraca, Francesca; Acharya, Kriti; Melillo, Bruno et al. (2016) Computational Evaluation of HIV-1 gp120 Conformations of Soluble Trimeric gp140 Structures as Targets for de Novo Docking of First- and Second-Generation Small-Molecule CD4 Mimics. J Chem Inf Model 56:2069-2079
Melillo, Bruno; Liang, Shuaiyi; Park, Jongwoo et al. (2016) Small-Molecule CD4-Mimics: Structure-Based Optimization of HIV-1 Entry Inhibition. ACS Med Chem Lett 7:330-4
Schön, Arne; Freire, Ernesto (2016) Enthalpy screen of drug candidates. Anal Biochem 513:1-6
Pustylnikov, Sergey; Dave, Rajnish S; Khan, Zafar K et al. (2016) Short Communication: Inhibition of DC-SIGN-Mediated HIV-1 Infection by Complementary Actions of Dendritic Cell Receptor Antagonists and Env-Targeting Virus Inactivators. AIDS Res Hum Retroviruses 32:93-100
Lee, Wen Shi; Richard, Jonathan; Lichtfuss, Marit et al. (2016) Antibody-Dependent Cellular Cytotoxicity against Reactivated HIV-1-Infected Cells. J Virol 90:2021-30
Madani, Navid; Princiotto, Amy M; Easterhoff, David et al. (2016) Antibodies Elicited by Multiple Envelope Glycoprotein Immunogens in Primates Neutralize Primary Human Immunodeficiency Viruses (HIV-1) Sensitized by CD4-Mimetic Compounds. J Virol 90:5031-46
Kalyana Sundaram, Ramalingam Venkat; Li, Huiyuan; Bailey, Lauren et al. (2016) Impact of HIV-1 Membrane Cholesterol on Cell-Independent Lytic Inactivation and Cellular Infectivity. Biochemistry 55:447-58
Schön, Arne; Freire, Ernesto (2016) Three easy pieces. Biochim Biophys Acta 1860:975-80
Herschhorn, Alon; Ma, Xiaochu; Gu, Christopher et al. (2016) Release of gp120 Restraints Leads to an Entry-Competent Intermediate State of the HIV-1 Envelope Glycoproteins. MBio 7:

Showing the most recent 10 out of 117 publications