Dependence of interferon induction on nucleic acid conformation.

UV and circular dichroism characteristics of duplex analogs belonging to the (A)n-(U)n and (I)n-(C)n series were determined to assign qualitatively the nature of conformational differences caused by 5-pyrimidine and c7 purine substitutions in such duplexes. Evidence is presented which shows that 5-pyrimidine substitution by bromine 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 two series. To wit, it is proposed that in the duplexes the effect of the change (A)n leads to (c7A)n is an increase of the positive base tilt, whereas the change (I)n leads to (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 proved to be useful as a sensor strand for the intepretation of the spectroscopic data. The circular dichroism findings correlate well with observations made earlier on the interferon inducing ability for such duplexes, namely, duplexes based on the (c7A)n are inactive as interferon inducers, whereas duplexes based on (c7I)n are potent inducers. Furthermore, 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-(br5U)n. Thus, this study provides the first 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 is dependent on the recognition of a particular spatial and steric organization of a double-stranded RNA.