Molecular Pharmacology, Vol 12, 844-853, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

Polyxanthylic and Polyguanylic Acid Inhibition of Murine Leukemia Virus Activities

¹ Department of Medical Viral Oncology, Roswell Park Memorial Institute, and Graduate Faculty in Microbiology, State University of New York at Buffalo, Roswell Park Division, Buffalo, New York 14263
² Department of Biochemical and Biophysical Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland 21205

Single-stranded polyribonucleotides inhibit the replication of murine leukemia virus (MuLV) in cultured cells. Our previous studies suggested that (a) purine polyribonucleotides may be more potent than pyrimidine polyribonucleotides, and (b) the inhibitory potency depends on the functional groups on the pyrimidine ring. In our earlier studies, a set of polyribonucleotides was not available which differed only in their purine as opposed to pyrimidine base; thus we could not clearly differentiate the effect of the base from that of the functional groups on the ring system. Poly(xanthylic acid) now provides the means to accomplish this. It is a purine polyribonucleotide with the same functional groups as poly(uridylic acid), a pyrimidine polyribonucleotide. Similarly, poly(guanylic acid) can be compared with poly(cytidylic acid), although the disposition of the functional groups is not identical in this case. We now report that poly(xanthylic acid) is, in fact, 2-3 times more potent than poly(uridylic acid) as an inhibitor of MuLV replication, and poly(guanylic acid) is similarly more potent than poly(cytidylic acid). Neither poly(xanthylic acid) nor poly(guanylic acid) significantly affects the growth rates of cultured host cells; thus their inhibition is apparently not related to any general cytotoxicity. Poly(xanthylic acid) as well as poly(guanylic acid) strongly inhibits MuLV-associated, RNA-directed DNA polymerase in vitro. They also inhibit host cell DNA polymerase activities in vitro, but analysis of inhibition kinetics shows that their inhibitor potency for viral DNA polymerase is several times greater than for cell DNA polymerases. These results substantiate our hypothesis that purine polyribonucleotides are more potent than pyrimidine polyribonucleotides. They also support the notion that inhibition of virus replication by polyribonucleotides may be related to their selective inhibition of viral RNA-directed DNA polymerase activity.

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ACKNOWLEDGMENTS We thank Ms. C. Hejna and Mr. A. Cairo for technical assistance, and Drs. B. I. Milavetz and J. S. Horoszewicz for providing a partially purified preparation of murine leukemia virus DNA polymerase.