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.
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-piperidinylcarbonyl)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.
Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA.
Isaac
I
Zentner
Luz-Jeannette
LJ
Sierra
Ayesha K
AK
Fraser
Lina
L
Maciunas
Marie K
MK
Mankowski
Andrei
A
Vinnik
Peter
P
Fedichev
Roger G
RG
Ptak
Julio
J
Martín-García
Simon
S
Cocklin
D000083:Acetanilides / Q000737:chemistry / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002478:Cells, Cultured; D057809:HEK293 Cells; D015488:HIV Antigens / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000378:metabolism; D062105:Molecular Docking Simulation; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
C583085:2-(4-((3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl)methyl))-1-piperazinyl-N-(4-methylphenyl)acetamide; D000083:Acetanilides; D019380:Anti-HIV Agents; D015488:HIV Antigens; D010069:Oxadiazoles; D019269:Phosphatidylinositol 4,5-Diphosphate; D011994:Recombinant Proteins; D054852:Small Molecule Libraries; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1