HPMPA

The cychc phosphonate of ( -HPMPA, [( -cHPMPA [106941-26-8], C H 2N50 P, 28] also is active against HSV-1 and HSV-2 infection in mice. Both (27) and (28) are reported to be efficacious against adenovims, vaccinia vims, as weU as variceUa-2oster vims infections (58). 

The mode of action of PMEA may be quite similar to the mechanism by which (3)-HPMPA accomplishes its selective inhibitory activity against herpes vimses. Eor PMEA to reach its active triphosphate form, it needs only two phosphorylation steps. The triphosphate derivative of PMEA has a much stronger affinity for HIV-1 reverse transcriptase than for cellular DNA polymerases (175). Whether it is actually incorporated into DNA and terminates the growing DNA chain is currentiy under investigation. 

The prototype member of the ANPs is (5)-9-(3-hydroxy-2-phosphonyl-methoxypropyl)adenine (HPMPA) (Fig. 2), first described for its broad-spectrum anti-DNA virus activity in 1986 (De Clercq et al. 1986). Then followed by the description of various other acyclic nucleoside phosphonates in 1987 (De Clercq et al. 1987). At present three acyclic nucleoside phosphonates have been licensed for clinical use cidofovir, adefovir, and tenofovir (Fig. 2). 

Dal Pozzo F, Andrei G, Lebeau I, Beadle JR, Hostetler KY, De Clercq E, Snoeck R (2007) In vitro evaluation of the anti-orf virus activity of alkoxyalkyl esters of CDV, cCDV and (S)-HPMPA. Antiviral Res 75 52-57... 

Wyles DL, Schooley RT, Kaihara KA, Beadle JR, Hostetler KY (2008) Anti-hepatitis C virus repli-con activity of alkoxyalkyl esters of (S)-HPMPA and other acyclic nucleoside phosphonates. In Abstracts of the 21st international conference on antiviral research, Montreal, QC, Canada, 13-17 April 2008. Antiviral Res 78 A21, no 15... 

Adenine Derivatives. These include (5)-9-(3-hydroxy-2-phosphonyl-methoxypropyl) adenine [(5 )-HlJMl AJ, CyH NjOsl (11), the cychc phosphonate of (S)-HPMPA, (S)-cHPMPA, G Hi2N504P (12). (S)-DHPA, C8H N,02 (13), and adeninylhydroxypropanoic acid alkyl esters [(R,S)-AHPA esters] (14) (Fig. 2). 

Resistance of HSV and CMV strains to PFA are owing to mutations in the DNA polymerase gene. The authors have shown a significant degree of crossresistance between PFA and the phosphonylmethoxyethyl (PME) derivatives of adenine (PMEA) and 2,6-diaminopurine (PMEDAP) on the one hand, and between HPMPC and HPMPA on the other (9,10). Although observed in the laboratory, resistance to cidofovir has not yet been documented in the clinic following treatment of CMV or HSV infections. 

It is possible that the virus mutant selected under the pressure of a certain drug is a mixture of two or more populations of virus. It has been found that the HSV-1 mutants arising under the selective pressure of HPMPC or HPMPA are not pure populations. Thus, plaque-purified virus must be prepared, and the drug-susceptibility profile of a few classes of compounds should be determined as well as the mutations in the drug-targeted viral gene that are associated with the resistant phenotype. 

Peterson LW, Sala-Rabanal M, Krylov IS, Serpi M, Kashemirov BA, McKenna CE (2010) Serine side chain-linked peptidomimetic conjugates of cyclic HPMPC and HPMPA synthesis and interaction with hPEPTl. Mol Pharm 7 2349-2361... 

Zakharova VM, Serpi M, Krylov IS, Peterson LW, Breitenbach JM, Borysko KZ, Drach JC, Collins M, Hilfinger JM, Kashemirov BA et al (2011) Tyrosine-based l-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) prodmgs synthesis, stability, antiviral activity, and in vivo transport smdies. J Med Chem 54 5680-5693... 

Nucleotide analogues such as 210, which are structurally related to the acyclonucleoside HPMPA, have been reported from Holy s laboratory.268.26 >... 

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