Journal article
Identification of a Small-Molecule Inhibitor of HIV-1 Assembly that Targets the Phosphatidylinositol (4,5)-bisphosphate Binding Site of the HIV-1 Matrix Protein
ChemMedChem, v 8(3), pp 426-432
Mar 2013
PMID: 23361947
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
The development of drug resistance remains a critical problem for current HIV-1 antiviral therapies, creating a need for new inhibitors of HIV-1 replication. We previously reported on a novel anti-HIV-1 compound,
N
2
-(phenoxyacetyl)-
N
-[4-(1-piperidinyl-carbonyl)benzyl]glycinamide (
14
), that binds to the highly conserved phosphatidylinositol (4,5)-bisphosphate (PI(4,5)P
2
)binding pocket of the HIV-1 matrix (MA) protein. In this study, we re-evaluate the hits from the virtual screen used to identify compound
14
and test them directly in an HIV-1 replication assay using primary human peripheral blood mononuclear cells. This study resulted in the identification of three new compounds with antiviral activity; 2-(4-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl})-1-piperazinyl)-
N
-(4-methylphenyl)-acetamide (
7
), 3-(2-ethoxyphenyl)-5-[[4-(4-nitrophenyl)piperazin-1-yl]methyl]-1,2,4-oxadiazole (
17
), and
N
-[4-ethoxy-3-(1-piperidinylsulfonyl)phenyl]-2-(imidazo[2,1-
b
][1,3]thiazol-6-yl)acetamide (
18
), with compound 7 being the most potent of these hits. Mechanistic studies on
7
demonstrated that it directly interacts with and functions through HIV-1 MA. In accordance with our drug target, compound
7
competes with PI(4,5)P
2
for MA binding and, as a result, diminishes the production of new virus. Mutation of residues within the PI(4,5)P
2
binding site of MA decreased the antiviral effect of compound
7
. Additionally, compound
7
displays a broadly neutralizing anti-HIV activity, with IC
50
values of 7.5–15.6 μm for the group M isolates tested. Taken together, these results point towards a novel chemical probe that can be used to more closely study the biological role of MA and could, through further optimization, lead to a new class of anti-HIV-1 therapeutics.
PIP
2
-ing HIV-1 to the post!
The discovery and characterization of a new small-molecule inhibitor (shown) of HIV-1 replication that targets the HIV-1 matrix (MA) protein is described. This novel agent exhibits a broad therapeutic spectrum, inhibiting all of the group M isolates tested, and functions via the novel mechanism of disrupting the critical phosphatidylinositol 4,5-bisphosphate (PI[4,5]P
2
)-MA interaction.
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Details
- Title
- Identification of a Small-Molecule Inhibitor of HIV-1 Assembly that Targets the Phosphatidylinositol (4,5)-bisphosphate Binding Site of the HIV-1 Matrix Protein
- Creators
- Isaac Zentner - Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102 (USA)Luz-Jeannette Sierra - Department of Microbiology & Immunology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102 (USA)Ayesha K Fraser - Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102 (USA)Lina Maciunas - Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102 (USA)Marie K Mankowski - Department of Infectious Disease Research, Southern Research Institute, 431 Aviation Way, Frederick, MD 21701 (USA)Andrei Vinnik - QuantumLead, Quantum Pharmaceuticals, Kosmonavta Volkova 6A-606, Moscow 125171 (Russia)Peter Fedichev - QuantumLead, Quantum Pharmaceuticals, Kosmonavta Volkova 6A-606, Moscow 125171 (Russia)Roger G Ptak - Department of Infectious Disease Research, Southern Research Institute, 431 Aviation Way, Frederick, MD 21701 (USA)Julio Martín-García - Department of Microbiology & Immunology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102 (USA)Simon Cocklin - Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102 (USA)
- Publication Details
- ChemMedChem, v 8(3), pp 426-432
- Publisher
- Wiley
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; Microbiology and Immunology
- Web of Science ID
- WOS:000315379200007
- Scopus ID
- 2-s2.0-84874297767
- Other Identifier
- 991014877809704721
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- Collaboration types
- International collaboration
- Web of Science research areas
- Chemistry, Medicinal
- Pharmacology & Pharmacy