title: Acylating drugs: redesigning natural covalent inhibitors.
abstract: Structural modification of naturally occurring beta-lactams and beta-lactones is a highly effective strategy for generating drugs for treating bacterial infections, cancer, obesity, and hyperlipidemia. These drugs acylate catalytic amino acids (serine, threonine, or cysteine) in enzyme targets such as penicillin-binding proteins (PBPs), beta-lactamases, lipases, HMG-CoA reductase, fatty acid synthetase, and the 20S proteasome. Optimally performing drugs combine features of high target affinity, chemoselective reactivity, and high stability of the acylated target protein. This review provides a perspective on these two classes of acylating agents and summarizes recent advances in mechanism and structure-based design of acylating drugs.
authors.affiliation: Avila Therapeutics, 100 Beaver Street, Waltham, MA 02453, USA.
authors.forename: Arthur F
authors.initials: AF
authors.lastname: Kluge
authors.forename: Russell C
authors.initials: RC
authors.lastname: Petter
mesh_terms: D000215:Acylation / Q000187:drug effects; D000818:Animals; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism; D046915:Penicillin-Binding Proteins / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams / Q000737:chemistry* / Q000378:metabolism
chemical_list: D007783:Lactones; D046915:Penicillin-Binding Proteins; D065093:beta-Lactamase Inhibitors; D047090:beta-Lactams