Dependence of interferon induction on nucleic acid conformation.

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Abstract
UV and circular dichroism characteristics of duplex analogs belonging to the (A)n.cntdot.(U)n and (I)n.cntdot.(C)n series were determined to assign qualitatively the nature of conformational differences caused by 5-pyrimidine and C7 [7-deaza-] purine substitutions in such duplexes. A 5-pyrimidine substitution by Br or methyl changes the duplex conformation of both series in a similar way, if at all. A c7 substitution in the purine ring affects the duplex conformation of the members in the same series similarly, but the conformational change appears to be different for the 2 series. Apparently, in the duplexes the effect of the change (A)n .fwdarw. (c7A)n is an increase of the positive base tilt, whereas the change (I)n .fwdarw. (c7I)n causes a decrease where (c7A)n is poly(7-deazaadenylic acid) and (c7I)n is poly(7-deazainosinic acid), respectively. Poly(5-bromocytidylic acid) (br5C)n was useful as a sensor strand for the interpretation of the spectroscopic data. The circular dichroism findings correlate well with observations made earlier on the interferon inducing ability for such duplexes, i.e., duplexes based on the (c7A)n are inactive as interferon inducers, whereas duplexes based on (c7I)n are potent inducers. A 5-pyrimidine substitution does not substantially affect the interferon inducing ability, unless the thermal stability of the analog becomes critical, as in the case of (A)n.cntdot.(br5U)n. Thus, this study provides the 1st evidence to link the interferon-inducing ability of a nucleic acid to a defined physical parameter of double helix, and reinforces the concept that interferon induction depends on the recognition of a particular spatial and steric organization of a double-stranded RNA.