Inhibition of Adenylyl Cyclase by Acyclic Nucleoside Phosphonate Antiviral Agents

Abstract

Acyclic derivatives of adenine, known as highly effective nucleotide analogs with broad spectrum antiviral activity, were evaluated for potential cross-reactivity with adenylyl cyclases, a family of membrane-bound enzymes that share putative topologies at their catalytic sites with oligonucleotide polymerases and reverse transcriptases. A series of derivatives of 9-(2-phosphonylmethoxyethyl)adenine (PMEA) inhibited a preparation of adenylyl cyclase derived from rat brain with IC 50 values that ranged from 66 M (PMEA) to 175 nM for its diphosphate derivative (PMEApp) and mimics of it. PMEApp mimics included PMEAp(NH)p, PMEAp(CH 2 )p, PMEAp(CX 2 )p (X ‫؍‬ fluorine, chlorine, 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 of some of these or similar compounds or constitute part of their side effects in therapeutic settings.Adenylyl cyclases are a family of membrane-bound enzymes central to one of the most important signal transduction systems and influence regulation of cell function in virtually all cells. The putative membrane topology of adenylyl cyclases conforms to a repeated sequence of a six-membrane spanning region followed by a cytosolic domain (1). The two cytosolic domains (C 1 and C 2 ) are homologous and contain regions that are highly conserved among adenylyl cyclase isozymes (1). The cleft formed by interaction of C 1 and C 2 contains the enzyme catalytic site (2, 3), the topology of which resembles aspects of the palm domain of DNA polymerases and human immunodeficiency virus (HIV) 1 reverse transcriptase (4 -7). Moreover, aspects of the catalytic mechanisms of adenylyl cyclases and enzymes involved in polymerization of oligonucleotides are similar as well. Each involves nucleoside triphosphate as substrate and divalent cation-dependent catalysis that includes attack involving the substrate 3Ј-OH group, to catalyze either chain elongation of a primer oligonucleotide or formation of the 3Ј:5Ј-cyclic phosphate, with pyrophosphate as a leaving group. Adenine nucleoside 3Ј-polyphosphates are among the most potent inhibitors of adenylyl cyclases (8 -11) and of these 2Ј-d-

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…However, as an off-target effect, certain antiviral compounds such as foscarnet and acyclic nucleoside phosphonates may inhibit mACs under clinical conditions (Shoshani et al, 1999;Kudlacek et al, 2001). It has been proposed that lithium and carbamazepine, mood stabilizers used for the treatment of bipolar disorder (Harwood and Agam, 2003), may act via preferential inhibition of AC5 (Mann et al, 2009).…”

Molecular Details of cAMP Generation in Mammalian Cells: A Tale of Two Systems

“…Foscarnet 131 and antiviral acyclic nucleoside derivatives of 9-(2-phosphonylmethoxyethyl)adenine 132 proved to be potent inhibitors of nucleotidyl cyclases, and these compounds may provide novel ideas for the development of specific inhibitors.…”

Small Ligands Modulating the Activity of Mammalian Adenylyl Cyclases: A Novel Mode of Inhibition by Calmidazolium

“…Recently, benzyloxybenzaldehyde analogs (Chang et al, 2001) and antiviral drugs, such as acyclic nucleotide phosphonates (Shoshani et al, 1999) and pyrophosphate analogs (Kudlacek et al, 2001), have also been shown to directly modulate AC activity.…”