The discovery of a class of novel HIV-1 maturation inhibitors and their potential in the therapy of HIV

Abstract

Although HIV infection is now primarily treated with reverse transcriptase and protease inhibitors, HIV therapy must look toward new drugs with novel mechanism(s) of action to both improve efficacy and address the growing problem of drug resistance. Using natural products as a source of biologically active compounds, our drug discovery program has successfully optimised the natural product betulinic acid to the first-in-class maturation inhibitor 3-O-(3',3'-dimethylsuccinyl)-betulinic acid (DSB). DSB's unique viral target has been identified as a late step in Gag processing. Specifically, it inhibits the cleavage of the capsid precursor, CA-SP1, resulting in a block to the processing of mature capsid protein leading to a defect in viral core condensation. DSB represents a unique class of anti-HIV compounds that inhibit virus maturation and provide additional opportunities for anti-HIV therapy. In this review, the discovery of DSB and its mode of action are summarised. Anti-AIDS Agents part 64. For part 63 in the series, see YU D, LEE KH: Recent progress and prospects on plant-derived anti-HIV agents and analogs. In: Medicinal Chemistry of Bioactive Natural Products. XT Liang, WS Fang (Eds), Wiley, New York, USA (2005) (In Press).

Impact of Human Immunodeficiency Virus Type 1 Resistance to Protease Inhibitors on Evolution of Resistance to the Maturation Inhibitor Bevirimat (PA-457)

“…BVM disrupts HIV-1 infectivity by specifically inhibiting a late step in the Gag processing cascade (5,6,33,44), the cleavage of SP1 from the C terminus of CA (21,49). The inhibition of CA-SP1 cleavage prevents proper maturation and potently inhibits virion infectivity (21,40,49).…”

A Single Amino Acid Substitution in a Segment of the CA Protein within Gag That Has Similarity to Human Immunodeficiency Virus Type 1 Blocks Infectivity of a Human Endogenous Retrovirus K Provirus in the Human Genome

“…Amino acids in a segment extending from the extreme C terminus of HIV-1 CA to the immediate downstream SP1 peptide were crucial for viral particle maturation (1,24,35,45). Amino acids spanning CA to SP1 also appear to be the target for a potent inhibitor of HIV-1 particle maturation (3,30,42,(67)(68)(69)(70). The spacer region immediately downstream of the CA C terminus is also crucial for (25,31).…”

Plant‐Derived Natural Products Research in Drug Discovery

“…In summary, M3 shows potent viral load reduction, a strong safety profile (with no evidence of organ toxicity or clinical intolerance), no evidence of clinically significant drug interactions, and, quite importantly, no evidence of rapid resistance development, which is a primary cause for antiretroviral treatment failure (125)(126)(127) Phase IIb clinical trials began in 2006 and still are ongoing. One of the trial goals will be to determine an optimal dose of M3.…”