Chloroquine and primaquine inhibition of rat liver cell-free polynucleotide-dependent polypeptide synthesis.

Chloroquine and primaquine inhibited polypeptide formation directed by poly U and random poly A,G,U in a rat liver cell-free system. It was necessary to preincubate the drug and polynucleotide before addition to the cell-free system to observe this inhibition. These antimalarials also decreased the binding of poly U to ribosomes under these conditions. No inhibition of polypeptide syntheses or poly U binding to ribosomes was observed when the drugs and polynucleotides were added to the cell-free system separately. Chloroquine and primaquine apparently interacted with the free polynucleotide and prevented the subsequent formation of an active polynucleotideribosome complex. CHLOROQUINE and primaquine are aminoquinoline derivatives currently used for the prophylaxis and treatment of malaria. These drugs are known to bind to several forms of natural and synthetic nucleic acids, namely, DNA,le3 tRNA,‘s3p4 polydeoxyribonucleotides,3 and polyribonucleotides. 3 They also affect reactions involving nucleic acids. DNA and RNA polymerases from E. coli were inhibited by chloroquine and primaquine in vitro.5,6 By contrast, the aminoacylation of E. coli tryptophan tRNA was enhanced.7 The present studies were initiated to determine possible effects of chloroquine and primaquine on cell-free polypeptide synthesis. We observed that these antimalarials inhibited polypeptide formation directed by poly U and random poly A,G,U in a rat liver cell-free system when the drug and polynucleotide were preincubated before addition to the protein synthesis system. A similar preincubation inhibited the binding of poly U to ribosomes. No inhibition of either peptide bond formation or ribosome binding to poly U occurred when the drug and polynucleotide were added separately to the cell-free system. * The research reported in this paper was conducted by personnel of the U.S.A.F. School of Aerospace Medicine, Aerospace Medical Division, AFSC, United States Air Force, Brooks AFB, Texas. Further reproduction is authorized to satisfy the needs of the U.S. Government. The animals involved in this study were maintained in accordance with the Guide fir Laboratory Animal Facilities and Cure as published by the National Academy of Sciences-National Research Council. t A preliminary report of the results has appeared: R. ROSKOSKI, JR. and S. R. JASKUNAS, Fedn Proc. 28, 893 (1969). $ Present address: The Rockefeller University, New York, N.Y. 10021.