Identification of potent maturation inhibitors against HIV-1 clade C.
Antiretroviral therapy has led to a profound improvement in the clinical care of HIV-infected patients. However, drug tolerability and the evolution of drug resistance have limited treatment options for many patients. Maturation inhibitors are a new class of antiretroviral agents for treatment of HIV-1. They act by interfering with the maturation of the virus by blocking the last step in Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA by the viral protease (PR). The first-in-class maturation inhibitor bevirimat (BVM) failed against a subset of HIV-1 isolates in clinical trials due to polymorphisms present in the CA-SP1 region of the Gag protein. Sequence analysis indicated that these polymorphisms are more common in non-clade B strains of HIV-1 such as HIV-1 clade C. Indeed, BVM was found to be ineffective against HIV-1 clade C molecular clones tested in this study. A number of BVM analogs were synthesized by chemical modifications at the C-28 position to improve its activity. The new BVM analogs displayed potent activity against HIV-1 clade B and C and also reduced infectivity of the virus. This study identifies novel and broadly active BVM analogs that may ultimately demonstrate efficacy in the clinic.
Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, India.
Uddhav
U
Timilsina
Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, India.
Dibya
D
Ghimire
Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, India.
Bivek
B
Timalsina
DFH Pharma, Gaithersburg, MD 20886, USA.
Theodore J
TJ
Nitz
DFH Pharma, Gaithersburg, MD 20886, USA.
Carl T
CT
Wild
Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, MD 21702-1201, USA.
Eric O
EO
Freed
Faculty of Life Sciences and Biotechnology, South Asian University, New Delhi 110021, India.
Ritu
R
Gaur
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity; D006801:Humans; D017386:Sequence Homology, Amino Acid
D019380:Anti-HIV Agents