Inhibition of peptidyltransferase and possible mode of action of a dipeptidyl chloramphenicol analog

A dipeptidyl chloramphenicol analog, D-threo-2-(L-phenylalanylglycyl)amino-3-p-nitrophenyl-1,3-propanediol, has been prepared and examined as an inhibitor of ribosomal peptidyltransferase. The analog is a more effective inhibitor of poly (U,C) directed protein biosynthesis in an Escherichia coli cell-free system than chloramphenicol and shows inhibitory activity equal to the parent antibiotic in the transpeptidation reaction. These results and the common structural features of puromycin and this compound suggest a model for the binding modes of chloramphenicol and chloramphenicol analogs. This proposal invokes four major binding pockets at the A-site of the peptidyltransferase center.