Fumagillin suppresses HIV‐1 infection of macrophages through the inhibition of Vpr activity

Abstract

HIV-1 viral protein R (Vpr) is one of the human immunodeficiency virus type 1 encoded proteins that have important roles in viral pathogenesis. However, no clinical drug for AIDS therapy that targets Vpr has been developed. Here, we have established a screening system to isolate Vpr inhibitors using budding yeast cells. We purified a Vpr inhibitory compound from fungal metabolites and identified it as fumagillin, a chemical already known to be a potent inhibitor of angiogenesis. Fumagillin not only reversed the growth inhibitory activity of Vpr in yeast and human cells, but also inhibited Vpr-dependent viral gene expression upon the infection of human macrophages.

Chemical Biology Based on Small Molecule–Protein Interaction

“…Using this indicator microorganism, we carried out a screen for a Vpr inhibitory compound from fungal metabolites. After many actinomycetes and fungal extracts were applied to this bioassay, we found inhibitory activity against Vpr in one fungal extract [9] and identified it as fumagillin, which already had been known as a potent inhibitor of angiogenesis [10]. Fumagillin not only suppressed the growth inhibitory activity of Vpr in yeast and human cells but also inhibited Vpr-dependent viral gene expression and HIV-1 virion production on viral infection of human macrophages.…”

RK-95113, a New Angiogenesis Inhibitor Produced by Aspergillus fumigatus

“…Meanwhile, it is not fully established why endothelial cell growth requires MetAP2, although the ability of fumagillin and its analogues to inhibit endothelial cell growth is related to their ability to inhibit MetAP2 activity in a p53-dependent manner [22,23]. Moreover, very recently we found that fumagillin and TNP-470 suppress human immunodeficiency virus I (HIV-1) infection of macrophages though the inhibition of HIV-1 viral protein R (VPR) activity, independently from the MetAP2 pathway [24]. Therefore, further comprehensive chemical and biological studies of fumagillin and its analogues, including RK-95113, might shed light on these pivotal events in relation to chemotherapy for angiogenesis-related diseases as well as for HIV-1.…”

“…The molecular formula of RK-95113 was determined to be C 24 (Fig. 1b), H-11 through H-13 and H-2Ј through H-8Ј, indicated the presence of an alkenyl moiety including a terminal methyl proton.…”

Syntheses of Fumagillin and Ovalicin

“…More recently, fumagillin (1) has been found to reverse the growth inhibitory activity of Viral protein R (Vpr) in yeast and human cells, and to inhibit the HIV-1 infection of human macrophages. [13] Structurally, these compounds are all comprised of a cyclohexane framework, two epoxides, and five or six contiguous stereogenic centers, three or four of which are situated on the cyclohexane ring. As a result of their unique structures and important biological properties, the fumagillins and ovalicins, as well as their congeners, have been pursued as attractive synthetic targets.…”