Inhibition of adenylyl cyclase by acyclic nucleoside phosphonate antiviralagents

Acyclic derivatives of adenine, known as highly effective nucleotide analog s with broad spectrum antiviral activity, were evaluated for potential cros s-reactivity with adenylyl cyclases, a family of membrane-bound enzymes tha t share putative topologies at their catalytic sites with oligonucleotide p olymerases and reverse transcriptases. A series of derivatives of 9-(2-phos phonylmethoxyethyl)adenine (PMEA) inhibited a preparation of adenylyl cycla se derived from rat brain with IC50 values that ranged from 66 mu M (PMEA) to 175 nM for its diphosphate derivative (PMEApp) and mimics of it. PMEApp mimics included PMEAp(NH)p, PMEAp(CH2)p, PREAp(CX2)p (X = fluorine, chlorin e, or bromine), PMEAp(CHX)pp, and PMEAp(C(OH)CH(3)pp. The data suggest that inhibition of adenylyl cyclases may contribute to the therapeutic action o f some of these or similar compounds or constitute part of their side effec ts in therapeutic settings.