Interferon Induction by a 2′‐Modified Double‐Helical RNA, Poly(2′‐azido‐2′‐deoxyinosinic acid) · polycytidylic acid

Abstract

Although the presence of free 2'-hydroxyl groups in both strands of a double-stranded RNA complex has been recognized as one of the major requisites for the interferon-inducing activity of double-stranded RNAs, we have found a particular analogue of (I), . (C), in which the 2'-hydroxyls of the purine nucleotide strand were replaced by azido groups, (dInj), . (C),, to be highly effective in inducing interferon. Various other 2'-azido analogues of (I), .

Interferon induction: a conformational hypothesis.

“…A comparison of calculations on 2'-deoxyadenosine from two different sets of starting coordinates reveals that substantial glycosidic conformational effects can be attributed to ribose conformation (9,10). Polydeoxynucleotide duplexes are inactive as interferon inducers apparently because of conformational effects associated with removal of the 2'-OH group (4,5,15). Interferon production is apparently dependent on the recognition of the overall conformation of the polynucleotide rather than on the binding of specific functional groups such as the 2'-OH group or the N7 nitrogen (5,15).…”

“…Polydeoxynucleotide duplexes are inactive as interferon inducers apparently because of conformational effects associated with removal of the 2'-OH group (4,5,15). Interferon production is apparently dependent on the recognition of the overall conformation of the polynucleotide rather than on the binding of specific functional groups such as the 2'-OH group or the N7 nitrogen (5,15). The calculation of the glycosidic 1018…”

“…Removal of the 2'-OH group without a conformationally equivalent replacement with respect to its effect on ribose puckering can destabilize the high anti conformations (10) and result in a loss of interferon-inducing potency (15). Similarly, replacement of the nitrogen at the 7 position in adenosine or in inosine by a -CH group results in divergent effects on glycosidic conformational profiles.…”

Antiviral Drug Development – Success and Failure: A Personal Perspective with a Japanese Connection

“…Various 2′-modified poly(I).poly(C) analogues were synthesized, for example, poly(2′-azido-2′-deoxyinosinic acid).poly(cytidylic acid) [6] and poly(2′-fluoro-2′-deoxyinosinic acid).poly(cytidylic acid) [7]. However, these compounds, which originated from a collaborative effort with Ikehara [6,7], were not further pursued for their therapeutic potential, because with the cloning of interferon, the clinicians' attention had in the meantime shifted from the endogenous induction of interferon to exogenously applied interferon. Exogenous interferon-a and -b would later prove useful in the treatment of chronic hepatitis C and multiple sclerosis, respectively.…”

Polynucleotides. L. Synthesis and properties of poly (2′ - chloro - 2′ - deoxyadenylic acid) and poly (2′ - bromo - 2′ - deoxyadenylic acid)

“…The fact that poly (2'-azido-2'-deoxyinosinicacid) 8,6and poly (2'-chloro-2'-deoxyinosinic acid) 16, when complexed with poly (C), are active as interferon inducers is a very interesting reflection of the structure-function relationship of such polynucleotides.…”