Inhibition of herpes simplex virus type 1 ribonucleotide reductase by substituted tetrapeptide derivatives.
It is known that peptides corresponding to the C-terminus of the small subunit of herpes simplex virus type 1 and 2 ribonucleotide reductase can inhibit enzymatic activity by preventing the association of the enzyme's two subunits. In a quest for smaller, more potent inhibitors, we have conducted a structure activity investigation based on the pentapeptide H-Val-Val-Asn-Asp-Leu-OH. Potency increases of up to 4000 times (IC50 0.18 microM) have been achieved in an enzymatic assay by a combination of modifying the N-terminal valine to a diethylacetyl group, adding a methyl group to the beta-carbon of the adjacent valine, dialkylating the asparagine side-chain nitrogen and dimethylating the beta-carbon of the aspartic acid residue. In addition the relative contribution of various inhibitor functionalities to inhibitor potency has been investigated.
Moss
N
N
Bio-Méga/Boehringer Ingelheim Research Inc., Laval, Québec, Canada.
Déziel
R
R
Adams
J
J
Aubry
N
N
Bailey
M
M
Baillet
M
M
Beaulieu
P
P
DiMaio
J
J
Duceppe
J S
JS
Ferland
J M
JM
D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000737:chemistry; D018259:Herpesvirus 1, Human / Q000201:enzymology*; D008745:Methylation; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D011759:Pyrrolidines / Q000737:chemistry; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D009842:Oligopeptides; D011759:Pyrrolidines; D001224:Aspartic Acid; D012264:Ribonucleotide Reductases; C032519:pyrrolidine