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Molecular Pharmacology, Vol 12, 299-312, Copyright © 1976 by the American Society for Pharmacology and Experimental Therapeutics

An Integrated and Comparative Study of the Antiviral Effects and Other Biological Properties of the Polyinosinic Acid-Polycytidylic Acid and Its Mismatched Analogues

PAUL O. P. TS’O 1, JAMES L. ALDERFER 1, JUDITH LEVY 1, LEWIS W. MARSHALL 2, JUDITH O’MALLEY 3, JULIUS S. HOROSZEWICZ 3, and WILLIAM A. CARTER 3

1 Division of Biophysics, Department of Biochemical and Biophysical Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, Maryland 21205
2 Department of Medicine, Howard University, Washington, D. C. 20001
3 Department of Medical Viral Oncology, Roswell Park Memorial Institute, Buffalo, New York 14263

Extensive investigations were made of the biological properties of the polynucleotide duplex, rIn·rCn, along with two modified duplexes having mismatched base pairs, rIn·r(C12,U)n [as well as rIn·r(C13,U)n] and rIn·r(C29,G)n5 [as well as rIn·r(C20,G)n]. These duplexes were studied using a variety of biological systems to determine their efficacy in producing antiviral activity (e.g., interferon) relative to their accompanying secondary biological properties (e.g. , acute toxicity, pyrogenicity, and mitogenic activity). These duplexes were studied on a comparative basis in the mouse for their ability to elicit protection against a lethal viral challenge, their acute toxicity, and their relative mitogenic effects on splenic cells. In the intact rabbit, circulating interferon and pyrogenicity were studied, and complementary studies were done with rabbit kidney cells in culture. In human neonatal fibroblasts in culture, these duplexes were studied for their antiviral protection and relative levels of interferon production. Our results indicate that the mismatched polynucleotide duplexes are comparable in their antiviral properties to rIn·rCn but possess much less pronounced secondary effects than the rIn·rCn molecule. The utility of these duplexes in elucidating mechanisms of biological responses to double-stranded RNA is discussed along with the presentation of a theoretical framework for design and development of polynucleotide duplexes having a therapeutic efficacy greater than rIn·rCn.

Submitted on August 19, 1975




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