Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors.
Concomitant with the release of human immunodeficiency virus type 1 (HIV-1) particles from the infected cell, the viral protease cleaves the Gag polyprotein precursor at a number of sites to trigger virus maturation. We previously reported that a betulinic acid-derived compound, bevirimat (BVM), blocks HIV-1 maturation by disrupting a late step in protease-mediated Gag processing: the cleavage of the capsid-spacer peptide 1 (CA-SP1) intermediate to mature CA. BVM was shown in multiple clinical trials to be safe and effective in reducing viral loads in HIV-1-infected patients. However, naturally occurring polymorphisms in the SP1 region of Gag (e.g., SP1-V7A) led to a variable response in some BVM-treated patients. The reduced susceptibility of SP1-polymorphic HIV-1 to BVM resulted in the discontinuation of its clinical development. To overcome the loss of BVM activity induced by polymorphisms in SP1, we carried out an extensive medicinal chemistry campaign to develop novel maturation inhibitors. In this study, we focused on alkyl amine derivatives modified at the C-28 position of the BVM scaffold. We identified a set of derivatives that are markedly more potent than BVM against an HIV-1 clade B clone (NL4-3) and show robust antiviral activity against a variant of NL4-3 containing the V7A polymorphism in SP1. One of the most potent of these compounds also strongly inhibited a multiclade panel of primary HIV-1 isolates. These data demonstrate that C-28 alkyl amine derivatives of BVM can, to a large extent, overcome the loss of susceptibility imposed by polymorphisms in SP1.
Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Emiko
E
Urano
Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Sherimay D
SD
Ablan
Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Rebecca
R
Mandt
Chemical Synthesis Group, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Gary T
GT
Pauly
Chemical Synthesis Group, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Dina M
DM
Sigano
Chemical Synthesis Group, Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA.
Joel P
JP
Schneider
DFH Pharma, Gaithersburg, Maryland, USA.
David E
DE
Martin
DFH Pharma, Gaithersburg, Maryland, USA.
Theodore J
TJ
Nitz
DFH Pharma, Gaithersburg, Maryland, USA.
Carl T
CT
Wild
Virus-Cell Interaction Section, HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, USA efreed@nih.gov.
Eric O
EO
Freed
D000478:Alkylation; D000586:Amination; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002213:Capsid / Q000187:drug effects; D036022:Capsid Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000187:drug effects; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D008969:Molecular Sequence Data; D011110:Polymorphism, Genetic; D013329:Structure-Activity Relationship; D013386:Succinates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000821:virology; D014315:Triterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014771:Virion / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D053978:Pentacyclic Triterpenes
D019380:Anti-HIV Agents; D036022:Capsid Proteins; D013386:Succinates; D014315:Triterpenes; D054301:gag Gene Products, Human Immunodeficiency Virus; C479935:bevirimat; D053978:Pentacyclic Triterpenes