Given that SKI-1/S1P-dependent proteolytic cleavage of SREBPs is a master molecular switch for controlling host cell cholesterol homeostasis [41, 53] , we hypothesized that inhibiting SKI-1/S1P endoproteolytic activity in the secretory pathway would prevent HCV hijacking of host lipid metabolic pathways and thus compromise the virus lifecycle. Because of our previous success with engineering serine protease inhibitors (serpins) to develop effective and selective PC inhibitors [54, 55] , we hypothesized that engineering a naturally occurring serpin scaffold could also provide a powerful approach for developing selective SKI-1/S1P inhibitors. Serpins differ from non-serpin inhibitors in that they require a large inhibitor conformational change in order to trap proteases in an irreversible complex [56] . The conformational change is initiated by reaction of the active serine of the protease with the reactive center loop (RCL) of the serpin, which results in a covalent species involving an acyl ester linkage to the cO of the protease active site serine [57] . This cleaves the RCL, which then moves 71 Å to the opposite pole of the serpin, taking the tethered protease with it [57] .