Oligopeptide inhibition of class I ribonucleotide reductases.
Class I ribonucleotide reductases (RRs), which are well-recognized targets for cancer chemotherapeutic and antiviral agents, are composed of two different subunits, R1 and R2, and are inhibited by oligopeptides corresponding to the C-terminus of R2, which compete with R2 for binding to R1. These peptides specifically inhibit the RRs from which they are derived, and closely homologous RRs, but do not inhibit less homologous RRs. Here we review results obtained for oligopeptide inhibition of RRs from several sources, including related x-ray, NMR, and modeling results. The most extensive studies have been performed on herpes simplex virus-RR (HSV-RR) and mammalian-RR (mRR). A common model fits the data obtained for both enzymes, in which the C-terminal residue of the oligopeptide (Leu for HSV-RR, Phe for mRR) binds with high specificity to a narrow and deep hydrophobic subsite, and two or more hydrophobic groups at the N-terminal portion of the peptide bind to a broad and shallow second hydrophobic subsite. The studies have led to the development of highly potent and specific inhibitors of HSV-RR and promising inhibitors of mRR, and indicate possible directions for the development of inhibitors of bacterial and fungal RRs.
Cooperman
Barry S
BS
Department of Chemistry, University of Pennsylvania, Philadelphia, PA 19104-6323, USA. cooprman@pobox.upenn.edu
D000595:Amino Acid Sequence; D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000145:classification* / Q000378:metabolism; D013045:Species Specificity
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D012264:Ribonucleotide Reductases