Alkyl Amine Bevirimat Derivatives Are Potent and Broadly Active HIV-1 Maturation Inhibitors

Abstract

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.

Incorporation of Privileged Structures into Bevirimat Can Improve Activity against Wild-Type and Bevirimat-Resistant HIV-1

“…Hundreds of derivatives were thus produced. 11,12,26,28,30,32–34 Among them, 4 was found to be over 20-fold more potent than 2 against the BVM-R virus. However, the improved activity of 4 was achieved by connecting a rather bulky group, methyl nonanoyl-glutaminate, to the C-28 of 2 .…”

Mechanistic Studies and Modeling Reveal the Origin of Differential Inhibition of Gag Polymorphic Viruses by HIV-1 Maturation Inhibitors

“…[13–15] The first generation HIV-1 maturation inhibitor, bevirimat (BVM), was halted in development[16] due to lack of clinical response in subjects whose viruses contained certain polymorphic Gag variants present in ~50% of the subtype B population, with such variations common among non-subtype B HIV-1 viruses. [17–27] Despite this result, BVM provided proof of concept (POC) in the clinic [28,29] that HIV-1 maturation inhibitors (MIs) per se might provide an effective alternative, should a next generation agent possess suitable pan-genotypic coverage. [30–32]…”

Fullerenes in biology and medicine

“…The latter can bind to Gag and affect its processing or to CA, thus impairing core assembly. 42 Currently, there are no maturation inhibitors used clinically. 43 …”