Abstract
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.
Highlights
The human immunodeficiency virus type 1 (HIV-1) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS)
It has been reported that BVM is ineffective against a subset of HIV-1 clade B isolates with polymorphisms in Gag, the QVT motif in the SP1 region[15,16]
We aligned the capsid-spacer peptide 1 (CA-SP1) sequence of HIV-1 clade B with multiple HIV-1 clade C clones compiled in Los Alamos HIV-1 sequence database and found that these polymorphisms are naturally present in HIV-1 clade C (Fig. 1a,b)
Summary
The human immunodeficiency virus type 1 (HIV-1) is a lentivirus that causes acquired immunodeficiency syndrome (AIDS). Owing to the development of viral-drug resistance and adverse effects associated with currently available drug regimens there is a continuous need to explore new drug targets[5,6] In this regard, 3-0-(3′-3′-dimethylsuccinyl) betulinic acid (bevirimat or BVM), a maturation inhibitor (MI)[7], has been reported to be effective against drug-resistant HIV-1 isolates[8,9]. Bevirimat has a unique mechanism of action distinct from that of the known ARVs as it inhibits a single cleavage event, the final Gag processing step in which p25 (CA-SP1) is cleaved to p24 (CA) and SP1 resulting in immature and non-infectious virus This specificity of BVM suggested that HIV-1 Gag, rather than the PR, is the target of compound binding[8,10,11,12]. One of the analog showed antiviral activity against a multi-clade panel of HIV-1 isolates[23]
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