title: Insights into the activity of maturation inhibitor PF-46396 on HIV-1 clade C.
abstract: HIV maturation inhibitors are an emerging class of anti-retroviral compounds that inhibit the viral protease-mediated cleavage of the Gag, CA-SP1 (capsid-spacer peptide 1) peptide to mature CA. The first-in-class maturation inhibitor bevirimat (BVM) displayed potent activity against HIV-1 clade B but was ineffective against other HIV-1 clades including clade C. Another pyridone-based maturation inhibitor, PF-46396 displayed potent activity against HIV-1 clade B. In this study, we aimed at determining the activity of PF-46396 against HIV-1 clade C. We employed various biochemical and virological assays to demonstrate that PF-46396 is effective against HIV-1 clade C. We observed a dose dependent accumulation of CA-SP1 intermediate in presence of the compound. We carried out mutagenesis in the CA- SP1 region of HIV-1 clade C Gag and observed that the mutations conferred resistance against the compound. Many mutations inhibited Gag processing thereby reducing virus release in the absence of the compound. However, presence of PF-46396 rescued these defects and enhanced virus release, replication capacity and infectivity of HIV-1 clade C. These results put together identify PF-46396 as a broadly active maturation inhibitor against HIV-1 clade B and C and help in rational designing of novel analogs with reduced toxicity and increased efficacy for its potential use in clinics.
authors.affiliation: Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, India.
authors.forename: Dibya
authors.initials: D
authors.lastname: Ghimire
authors.affiliation: Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, India.
authors.forename: Uddhav
authors.initials: U
authors.lastname: Timilsina
authors.affiliation: Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, India.
authors.forename: Tryambak Pratap
authors.initials: TP
authors.lastname: Srivastava
authors.affiliation: Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, India.
authors.forename: Ritu
authors.initials: R
authors.lastname: Gaur
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D036022:Capsid Proteins / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D016333:HIV Protease / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D059748:Proteolysis / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D036022:Capsid Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease