SUMMARY

By comparative sequence analysis of the herpes simplex virus type 1 DNA polymerase gene of strain Angelotti and a phosphonoacetic a id-resistant (PAA9 derivative, the site of the PAA r mutation was identified as a single nucleotide (C--, T) conversion within the mapping limits of the known PAA r mutations of strains KOS and 17. The conservative amino acid change at residue 719 from alanine to valine results in a radical change in the properties of the polymerase, rendering the mutant enzyme resistant to PAA and various antiviral compounds. Amino acid homologies as well as secondary structure analysis reveal that the PAA ~ mutation is contained in a 14 amino acid sequence which is highly conserved, and detected in the central domain of prokaryotic and eukaryotic DNA polymerases. The herpes simplex virus (HSV) DNA polymerase r presents one of the major target enzymes of modern antiviral chemotherapy. The unique response of the enzyme towards antiherpetic drugs, and the ease by which drug-resistant variants with altered enzymic properties are isolated, have rendered the HSV polymerase gene an excellent model system for correlating genetic hanges with altered enzymic functions. Biochemical studies on the polymerase activit