The 3-O-(3',3'-dimethylsuccinyl) derivative of betulinic acid (DSB) inhibits the assembly of virus-like particles in HIV-1 Gag precursor-expressing cells

The 3-O-(3',3'-dimethylsuccinyl) derivative of betulinic acid (DSB) blocks HIV-1 maturation by interfering with viral protease (PR) at the capsid (CA)-SP1 cleavage site, a crucial region in HIV-1 morphogenesis. We analysed the effect of DSB on the assembly of HIV-1 Gag precursor (Pr55Gag(H...

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Bibliographic Details
Published in:Antiviral therapy 2007-01, Vol.12 (8), p.1185-1203
Main Authors: DAFONSECA, Sandrina, BLOMMAERT, Armand, CORIC, Pascale, SAW SEE HONG, BOUAZIZ, Serge, BOULANGER, Pierre
Format: Article
Language:English
Subjects:
Animals
Anti-HIV Agents
Anti-HIV Agents - pharmacology
Antibiotics. Antiinfectious agents. Antiparasitic agents
Antiviral agents
Baculoviridae
Baculoviridae - physiology
Biochemistry, Molecular Biology
Biological and medical sciences
Cell Line
Dose-Response Relationship, Drug
HIV-1
HIV-1 - drug effects
HIV-1 - metabolism
Human viral diseases
Immunodeficiencies
Immunodeficiencies. Immunoglobulinopathies
Immunopathology
Infectious diseases
Life Sciences
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Protein Precursors
Protein Precursors - chemistry
Protein Precursors - metabolism
Protein Structure, Tertiary
Spodoptera
Structural Biology
Structure-Activity Relationship
Succinates
Succinates - pharmacology
Triterpenes
Triterpenes - pharmacology
Viral diseases
Viral diseases of the lymphoid tissue and the blood. Aids
Virus Assembly
Virus Assembly - drug effects
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Summary:The 3-O-(3',3'-dimethylsuccinyl) derivative of betulinic acid (DSB) blocks HIV-1 maturation by interfering with viral protease (PR) at the capsid (CA)-SP1 cleavage site, a crucial region in HIV-1 morphogenesis. We analysed the effect of DSB on the assembly of HIV-1 Gag precursor (Pr55Gag(HIV)) into membrane-enveloped virus-like particles (VLP) in baculovirus-infected cells expressing Pr55Gag(HIV), in a cellular context devoid of viral PR. DSB showed a dose-dependent negative effect on VLP assembly, with an IC50 approximately 10 microM. The DSB inhibitory effect was p6-independent and was also observed for intracellular assembly of non-N-myristoylated Gag core-like particles. HIV-1 VLP assembled in the presence of DSB exhibited a lower stability of their inner cores upon membrane delipidation compared with control VLP, suggesting weaker Gag-Gag interactions. DSB also inhibited the assembly of simian immunodeficiency virus SLVmac251 VLP, although with a twofold lower efficacy (IC50 approximately 20 microM). No detectable inhibitory activity was observed for murine leukaemia virus (MLV) VLP; however, fusion of the SP1-NC-p6 domains from HIV-1 to the matrix (MA)-CA domains from MLV conferred DSB sensitivity to the chimaeric Gag precursor Pr72Gag(MLV-HIV) (IC50 = 30 microM). This observation suggested that the main DSB target on Pr55Gag was the SP1 domain, but the higher degree of DSB resistance for Pr72Gag(MLV-HIV) compared with Pr55Gag(HIV) implied that other upstream Gag region(s) might contribute to DSB reactivity. Sequence alignment and three-dimensional modelling by homology of the CA-SP1-NC junction in HIV-1, SLVmac251 and Pr72Gag(MLV-HIV) suggested that a higher hydrophilic character of the CA region immediately upstream to the HIV-1 CA-SP1 junction, as occurred in Pr72Gag(MLV-HIV), correlated with a lower DSB sensitivity.
ISSN:1359-6535
2040-2058
DOI:10.1177/135965350701200807