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. Issue 3 (29th January 2013)

• Record Type: Journal Article
• Authors: Zentner, Isaac; Sierra, Luz‐Jeannette; Fraser, Ayesha K.; Maciunas, Lina; Mankowski, Marie K.; Vinnik, Andrei; Fedichev, Peter; Ptak, Roger G.; Martín‐García, Julio; Cocklin, Simon
• Is Part Of: ChemMedChem. Volume 8:Issue 3(2013:Mar.)
• Page Start: 426
• Page End: 432
• Publication Date: 2013-01-29
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201200577
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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, <italic>N</italic><sup>2</sup>‐(phenoxyacetyl)‐<italic>N</italic>‐[4‐(1‐piperidinylcarbonyl)benzyl]glycinamide (<bold>14</bold>), that binds to the highly conserved phosphatidylinositol (4, 5)‐bisphosphate (PI(4, 5)P<sub>2</sub>) 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 <bold>14</bold> 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)‐<italic>N</italic>‐(4‐methylphenyl)acetamide (<bold>7</bold>), 3‐(2‐ethoxyphenyl)‐5‐[[4‐(4‐nitrophenyl)piperazin‐1‐yl]methyl]‐1, 2, 4‐oxadiazole (<bold>17</bold>), and <italic>N</italic>‐[4‐ethoxy‐3‐(1‐piperidinylsulfonyl)phenyl]‐2‐(imidazo[2, 1‐<italic>b</italic>][1, 3]thiazol‐6‐yl)acetamide (<bold>18</bold>), with compound <bold>7</bold> being the most potent of these hits. Mechanistic studies on <bold>7</bold> demonstrated that it directly interacts with and functions through HIV‐1 MA. In accordance with our drug target, compound <bold>7</bold> competes with PI(4, 5)P<sub>2</sub> for MA binding and, as a result, diminishes the production of new virus. Mutation of residues within the PI(4, 5)P<sub>2</sub> binding site of MA decreased the antiviral effect of compound <bold>7</bold>. Additionally, compound <bold>7</bold> displays a broadly neutralizing anti‐HIV activity, with IC<sub>50</sub> values of 7.5–15.6 μ<sc>M</sc> 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.</p> </abstract>