Abstract
HIV protease inhibitors (HIV-PIs) are key components of highly active antiretroviral therapy, but they have been associated with adverse side effects, including partial lipodystrophy and metabolic syndrome. We recently demonstrated that a commonly used HIV-PI, lopinavir, inhibits ZMPSTE24, thereby blocking lamin A biogenesis and leading to an accumulation of prelamin A. ZMPSTE24 deficiency in humans causes an accumulation of prelamin A and leads to lipodystrophy and other disease phenotypes. Thus, an accumulation of prelamin A in the setting of HIV-PIs represents a plausible mechanism for some drug side effects. Here we show, with metabolic labeling studies, that lopinavir leads to the accumulation of the farnesylated form of prelamin A. We also tested whether a new and chemically distinct HIV-PI, darunavir, inhibits ZMPSTE24. We found that darunavir does not inhibit the biochemical activity of ZMPSTE24, nor does it lead to an accumulation of farnesyl-prelamin A in cells. This property of darunavir is potentially attractive. However, all HIV-PIs, including darunavir, are generally administered with ritonavir, an HIV-PI that is used to block the metabolism of other HIV-PIs. Ritonavir, like lopinavir, inhibits ZMPSTE24 and leads to an accumulation of prelamin A.
Highlights
HIV protease inhibitors (HIV-PIs)3 are designed to inhibit the HIV aspartyl protease, which is required for generating viral
Prelamin A detected in extracts from HIV-PI-treated cells migrated more rapidly on SDS-polyacrylamide gels than prelamin A obtained after farnesyltransferase inhibitor (FTI) treatment
We found that the prelamin A that accumulates in lopinavir- and atazanavir-treated cells was farnesylated, as judged by the incorporation of AG (Fig. 1A)
Summary
HIV protease inhibitors (HIV-PIs) are designed to inhibit the HIV aspartyl protease, which is required for generating viral. In 2003, Caron et al [10] reported that a pair of HIV-PIs, indinavir and nelfinavir, appeared to lead to the accumulation of small amounts of prelamin A in a preadipocyte cell line. This finding was intriguing, but the biochemical mechanism was obscure. Rational drug design strategies have yielded potent HIV-PIs that are structurally unrelated to lopinavir One such compound, darunavir, exhibits very high affinity for the HIV protease and is potent in reducing viral loads [14]. We tested if darunavir inhibits ZMPSTE24 and leads to prelamin A accumulation in cells Because it blocks the metabolism of HIV-PIs, ritonavir increases drug levels and improves drug efficacy [15]
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