The saquinavir family of HIV aspartyl protease inhibitors, including lopinavir and atazanavir, can also affect the zinc metalloprotease involved in the maturation of prelamin A to lamin A (4). These inhibitors were designed as transition state inhibitors for HIV-encoded peptidyl substrates with a phenylalanine residue in the P1 site (1) and contain different chemical groupings at their ends, designated here as “bells” and “whistles.” The HIV protease is a soluble member of the aspartyl family of proteases; its active site is at the dimeric interface where the side-chain carboxylate of Asp-25 in one subunit functions as a base to deprotonate the hydrolytic water molecule, and the side-chain carboxylic acid in Asp-25 of the other subunit functions as an acid to activate the carbonyl group of the scissile peptide bond to create a transition state with tetrahedral geometry and structure that is matched by the inhibitor structure. Although the configuration at the – CH–OH– sites in lopinavir and atazanavir is S and that in saquinavir is R, the hydroxyl groups in all of these compounds can mimic one or the other of the two hydroxyl groups in the tetrahedral near-transition state. ZMPSTE24 is a membrane-associated zinc metalloprotease where a likely mechanism involves the metal ion binding to the hydrolytic water to lower its pK_a and to the scissile carbonyl oxygen to activate its carbon electrophile (5). Although there are similarities in the use of a carboxylate group and in the overall structure of the presumed transition state, it comes as a surprise that a specific HIV protease inhibitor would also inhibit ZMPSTE24 (4). This figure was prepared by Brian D. Young (University of California, Los Angeles).