Conversion of 1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl)methyl]cytosine to cidofovir by an intracellular cyclic CMP phosphodiesterase.

AUTOR(ES)

Mendel, D B

RESUMO

Cidofovir (HPMPC) [1-[(S)-3-hydroxy-2-(phosphonomethoxy)propyl]-cytosine] is an acyclic nucleotide analog with potent and selective activity against herpesviruses. The prodrug, cyclic HPMPC (cHPMPC) [1-[((S)-2-hydroxy-2-oxo-1,4,2-dioxaphosphorinan-5-yl) methyl]cytosine], has antiviral activity similar to that of the parent compound but exhibits reduced toxicity in animal models. cHPMPC is converted to cidofovir by a cellular cyclic CMP phosphodiesterase (EC 3.1.4.37) which hydrolyzes a variety of substrates, including adenosine 3',5'-cyclic monophosphate (cAMP) and cytidine 3',5'-cyclic monophosphate (cCMP). The K(m) and Vmax values for hydrolysis of cHPMPC by cCMP phosphodiesterase purified from human liver are 250 microM and 0.66 nmol.min-1.unit-1, respectively. These values are similar to the K(m) and Vmax values for cAMP (23 microM and 1.16 nmol.min-1.unit-1, respectively) and cCMP (75 microM and 2.32 nmol.min-1.unit of enzyme-1, respectively). The catalytic efficiency (Vmax/K(m) ratio) of this enzyme for the cHPMPC substrate is only 10- to 20-fold lower than those for the natural cyclic nucleotides, indicating that cHPMPC is a viable intracellular substrate for the human enzyme. Kinetic analysis indicates that cHPMPC, cAMP, and cCMP are competitive with respect to each other and that they are hydrolyzed by the same enzyme. cHPMPC is hydrolyzed to cidofovir in all primary human cell systems tested, including those derived from target organs that might be infected in patients with human cytomegalovirus (HCMV) disease. Importantly, hydrolysis of cHPMPC is not diminished in cells infected with HCMV.

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