WIN51711-RESISTANT MUTANTS OF POLIOVIRUS TYPE-3 - CAPSID RESIDUES IMPORTANT IN UNCOATING FUNCTIONS

Capsid-binding drugs that inhibit the first stage of picornaviral unco ating were used to select drug-resistant mutants of the Sabin strain o f poliovirus type 3. Such mutants provide information about parts of t he capsid that are important for functions blocked by the drugs, and a lso about pathways to drug resistance. Amino-acid substitutions allowi ng virus to produce progeny in the presence of drug were mapped to 13 different residues occupying three distinct locations: (I) the canyon base; (II) the lining of the drug-binding pocket; and (III) the base o f the protomer. These loci might be thought of as action points for tr ansmitting the uncoating signal from receptor, through the pocket, and to the base of the protomer. All of the mutations in a special class of drug-dependent mutants were clustered at site (III) and all were hy perlabile, i.e., uncoated spontaneously (without receptor) at growth t emperature unless prevented from doing so by the presence of drug in t he pocket. Thus, site (III) seems to represent a kind of thermostat wh ich regulates the temperature at which the uncoating transition (relea se of VP4 to form A particles) is triggered.