Interferon Induction by Two 2′‐Modified Double‐Helical RNAs, Poly(2′‐nuoro‐2′‐deoxymosimc acid) · poly(cytidylic acid) and Poly(2′‐chloro‐2′‐deoxyinosinic acid) · poly(cytidylic acid)

In addition to the 2′‐azido analogue of (I) n · (C) n , (dIn 3 ) n · (C) n , we have found two other (I) n · (C) n analogues, (dIfl) n · (C) n , and (dIcl) n · (C) n , in which the 2′‐hydroxyls of the (I) n strand are replaced by either fluorine or chlorine, to be highly effective in inducing interferon. This contrasted with the lack of interferon‐inducing activity noted for various other 2′‐halogeno analogues of (I) n · (C) n and (A) n · (U) n , i.e. (I) n · (dCcl) n (dAfl) n · (U) n , (dAcl) n · (U) n , (A) n · (dUfl) n and (A) n · (dUcl) n . In most assay systems, viz. primary rabbit kidney cells, human diploid fibroblasts, HeLa cells, interferon‐primed mouse L‐929 cells, and intact rabbits, (dIfl) n · (C) n and (dIcl) n · (C) n induced interferon levels that were comparable to those induced by (I) n · (C) n . There was one particular system (L‐929 cells treated with DEAE‐dextran), however, in which (dIfl) n · (C) n and (dIcl) n · (C) n , unlike (I) n · (C) n , failed to stimulate interferon production. As monitored by both radiochemical and biological means, (dIfl) n , · (C) n and, to a lesser extent, (dIcl) n · (C) n , were more resistant to degradation by ribonuclease A, T 1 and human serum nucleases than was (I) n · (C) n . In their reactivity towards antibodies to double‐stranded RNA (dIfl) n · (C) n and (dIcl) n · (C) n conformed more closely to (I) n · (C) n than did other 2′‐substituted (e.g. 2′‐ O ‐methyl or 2′‐ O ‐ethyl) analogues of (I) n · (C) n . The high interferon‐inducing potency of (dIfl) n · (C) n and (dIcl) n · (C) n has both theoretical and practical implications. While our findings suggest that (dIfl) n , · (C) n and (dIcl) n · (C) n should be further explored for their therapeutic potentials, they also strengthen the notion that the interferon‐inducing capacity, and possibly other biological functions of double‐stranded RNAs is dependent on the recognition of the overall conformation of the polynucleotide rather than on the binding of specific functional groups such as the 2′‐hydroxyl group.