INHIBITION OF HERPES-SIMPLEX VIRUS TYPE-1 RIBONUCLEOTIDE REDUCTASE BYSUBSTITUTED 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 e nzyme's two subunits. In a quest for smaller, more potent inhibitors, we have conducted a structure activity investigation based on the pent apeptide H-Val-Val-Asn-Asp-Leu-OH. Potency increases of up to 4000 tim es (IC50 0.18 muM) have been achieved in an enzymatic assay by a combi nation of modifying the N-terminal valine to a diethylacetyl group, ad ding a methyl group to the beta-carbon of the adjacent valine, dialkyl ating the asparagine side-chain nitrogen and dimethylating the beta-ca rbon of the aspartic acid residue. In addition the relative contributi on of various inhibitor functionalities to inhibitor potency has been investigated.