Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines.

Abstract

Three acyclic nucleoside phosphonates (ANPs) have been formally approved for clinical use in the treatment of 1) cytomegalovirus retinitis in AIDS patients (cidofovir, by the intravenous route), 2) chronic hepatitis B virus (HBV) infections (adefovir dipivoxil, by the oral route), and 3) human immunodeficiency virus (HIV) infections (tenofovir disoproxil fumarate, by the oral route). The activity spectrum of cidofovir {(S)- 1-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine [(S)-HPMPC)]}, like that of (S)-HPMPA [(S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]adenine) and (S)-HPMPDAP [(S)-9-[3-hydroxy-2-(phosphonomethoxy)propyl]-2, 6-diaminopurine), encompasses a broad spectrum of DNA viruses, including polyoma-, papilloma-, adeno-, herpes-, and poxviruses. Adefovir {9-[2-(phosphonomethoxy)ethyl]adenine (PMEA)} and tenofovir [(R)-9-[2-(phosphonomethoxy) propyl]adenine [(R)-PMPA)]} are particularly active against retroviruses (ie., HIV) and hepadnaviruses (ie., HBV); additionally, PMEA also shows activity against herpes- and poxviruses. We have recently identified a new class of ANPs, namely 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines, named, in analogy with their alkylpurine counterparts, HPMPO-DAPy, PMEO-DAPy, and (R)-PMPO-DAPy. These compounds exhibit an antiviral activity spectrum and potency that is similar to that of (S)-HPMPDAP, PMEA, and (R)-PMPA, respectively. Thus, PMEO-DAPy and (R)-PMPO-DAPy, akin to PMEA and (R)-PMPA, proved particularly active against HIV- 1, HIV-2, and the murine retrovirus Moloney sarcoma virus (MSV). PMEO-DAPy and (R)-PMPO-DAPy also showed potent activity against both wild-type and lamivudine-resistant strains of HBV. HPMPO-DAPy was found to inhibit different poxviruses (ie., vaccinia, cowpox, and orf) at a similar potency as cidofovir. HPMPO-DAPy also proved active against adenoviruses. In vivo, HPMPO-DAPy proved equipotent to cidofovir in suppressing vaccinia virus infection (tail lesion formation) in immunocompetent mice and promoting healing of disseminated vaccinia lesions in athymic-nude mice. The 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines offer substantial potential for the treatment of a broad range of retro-, hepadna-, herpes-, adeno-, and poxvirus infections.

• Authors: Erik De Clercq, G Andrei, J Balzarini, P Leyssen, L Naesens, J Neyts, C Pannecouque, R Snoeck, C Ying, D Hocková, A Holý
• Journal: Nucleosides, nucleotides & nucleic acids (Nucleosides Nucleotides Nucleic Acids) Vol. 24 Issue 5-7 Pg. 331-41 ( 2005) ISSN: 1525-7770 [Print] United States
• PMID: 16247948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-HIV Agents
• Antiviral Agents
• Organophosphonates
• Purines
• Pyrimidines
• 2,4-diaminopyrimidine
• Cytosine
• Cidofovir

Topics

• Adenoviridae (metabolism)
• Adenoviridae Infections (drug therapy)
• Animals
• Anti-HIV Agents (chemical synthesis, pharmacology)
• Antiviral Agents (chemical synthesis, pharmacology)
• Cell Line
• Cidofovir
• Cytosine (analogs & derivatives, pharmacology)
• HIV Infections (drug therapy)
• Humans
• Mice
• Mice, Nude
• Models, Chemical
• Moloney murine sarcoma virus (metabolism)
• Organophosphonates (chemical synthesis, pharmacology)
• Papillomaviridae (metabolism)
• Papillomavirus Infections (drug therapy)
• Poxviridae (metabolism)
• Poxviridae Infections (drug therapy)
• Purines (chemistry)
• Pyrimidines (chemical synthesis, pharmacology)
• Vaccinia (drug therapy)
• Vaccinia virus (metabolism)