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).

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Program Projects (P01)
Project #
2P01GM056550-17A1
Application #
8603509
Study Section
Special Emphasis Panel (ZRG1-AARR-E (43))
Project Start
Project End
Budget Start
2013-09-30
Budget End
2014-08-31
Support Year
17
Fiscal Year
2013
Total Cost
$218,235
Indirect Cost
$79,119
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:

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