“…The reactivity of simple FPs, derived from the strongly polarized phosphorus–fluorine bond, has found use in chemical nerve agents (sarin, soman) and insecticides (diisopropylfluorophosphate-DFP) as general SH inhibitors marked by unfettered enzyme promiscuity. Early investigations integrating the FP warhead into simple amino acid analogues, however, demonstrated that modest selectivity for chymotrypsin, elastase, or trypsin-like enzymes was achievable depending on side-chain identity (Bartlett and Lamden, 1986; Lamden and Bartlett, 1983; Ni and Powers, 1998). Indeed, even largely aliphatic FP probes resembling substrates of diacylglycerol lipases or ghrelin esterases were found to selectively inhibit specific SHs with minimal off-target reaction (Bisogno et al, 2013; Eubanks et al, 2011).…”