Structure-function Studies of Peptides Inhibiting the Ribonucleotide Reductase Activity of Herpes Simplex Virus Type I

J Med Chem. 1992 Jan 24;35(2):346-50. doi: 10.1021/jm00080a021.

Abstract

Ac-Tyr298-Ala299-Gly300-Thr301-Val302-I le303-Asn304-Asp305-Leu306-OH (Ac-VZV R2-(298-306)) represents the acetylated form of the C-terminus of varicella-zoster virus (VZV) ribonucleotide reductase subunit 2 (R2). This peptide possesses a high degree of homology with the C-terminus nonapeptide of the herpes simplex virus (HSV) type I and II ribonucleotide reductase R2 protein and is 15 times more potent than the latter in its in vitro inhibition of HSV-1 reductase activity. Accordingly, a new series of analogues based on this structure was studied in vitro. The replacement of Asp305 by Asn, Glu, Gln, Ser, or Cys; of Asn304 by Gln or Ser; of Ile303 and Val302 by D-Val; and of Tyr298 by Cha induced an important loss of inhibitory potency. The substitution of Asn304 by Asp; of Thr301 by Cys, Ser, or Val; of Gly300 by Ala or Val; of Ala299 by Val; or of Tyr298 by homoPhe, 4'-fluoro-Phe, 4'-chloro-Phe, 3'-iodo-Tyr, Me-Tyr, or For-Trp led to a moderate decrease of the Ac-VZV R2-(298-306) potency. The replacement of Val302 by Ile; Ala299 by Cys, Ser, or Thr; or the insertion of a six- or eight-carbon chain between Tyr298 and the NH2 terminus either preserved or slightly increased the inhibitory potency of Ac-VZV R2-(298-306). Finally, the substitution of Tyr298 by Trp or the addition of 4'-nitro-Phe at the amino terminus resulted in a 3-fold increase of potency. Altogether, these results stress the importance of the structural integrity of the minimum active core 302-306 in preserving the inhibitory potency and suggest that further studies on monosubstitutions could be directed at the portion 298-301 of the peptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Chromatography, High Pressure Liquid
  • Molecular Sequence Data
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Ribonucleotide Reductases / antagonists & inhibitors*
  • Ribonucleotide Reductases / chemical synthesis*
  • Ribonucleotide Reductases / chemistry
  • Simplexvirus / enzymology*
  • Structure-Activity Relationship

Substances

  • Peptide Fragments
  • Ribonucleotide Reductases