Interferon induction by poly(inosinic acid).cntdot.poly(cytidylic acid) segmented by spin-labels

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Abstract
Poly(inosinic acid) .cntdot. poly(cytidylic acid) [(I)n .cntdot. (C)n] duplexes of which the (C)n strand was modified to various degrees chemically or enzymatically with nitroxide radicals (spin-labels) were evaluated for interferon-inducing activity. Upon annealing of the chemically modified (C)n, (lC,Cx)n (x = 1000 or 16), with (I)n, the interferon-inducing activity was similar to that of (I)n .cntdot. (C)n in PRK [primary rabbit kidney] cell cultures. To overcome hydrolysis of the spin-label linkage in (lC,Cx)n, an enzymatic approach was taken to synthesize (ls4U,Cx)n copolymers with x = 100, 38, 16 and 8. The (ls4U,Cx)n copolymers were chemically stable, and upon annealing with (I)n the correlation time of the nitroxide moiety in (I)n .cntdot. (ls4U,Cx)n was determined. A comparison of this correlation time with that measured for (RUGT,U100)n .cntdot. (A)n, which contains the nitroxide moiety in position 5 of the U moiety, suggests that the ls4U residue is in a nonintrahelical conformation and partitions the duplex into double-helical segments of varying size. The interferon-inducing activity of (I)n .cntdot. (ls4U,Cx)n was evaluated in PRK, human skin fibroblast (strain VGS) and mouse L-929 cell cultures as well as in rabbits. The ls4U residue did not cause a significant change in the interferon induction as compared to (I)n .cntdot. (C)n in most systems tested unless x < 16. Double-helical segments of .apprx. 16 base pairs partitioned by nonintrahelical ls4U residues suffice to trigger the interferon response in all systems studied.

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