ANTIVIRAL POTENTIAL OF A NEW GENERATION OF ACYCLIC NUCLEOSIDE PHOSPHONATES, THE 6-[2-(PHOSPHONOMETHOXY)ALKOXY]-2,4-DIAMINOPYRIMIDINES
| Autor: | Robert Snoeck, Pieter Leyssen, Graciela Andrei, Johan Neyts, Christophe Pannecouque, Dana Hocková, Lieve Naesens, Erik De Clercq, Antonín Holý, Chunxiao Ying, Jan Balzarini |
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| Rok vydání: | 2005 |
| Předmět: |
Moloney Sarcoma Virus
Anti-HIV Agents Adenoviridae Infections viruses Cowpox Moloney murine sarcoma virus Organophosphonates Mice Nude HIV Infections Vaccinia virus Poxviridae Infections Antiviral Agents Biochemistry Virus Adenoviridae Cell Line Cytosine Mice chemistry.chemical_compound Retrovirus Vaccinia Genetics medicine Adefovir Animals Humans Poxviridae Papillomaviridae biology Chemistry Papillomavirus Infections virus diseases General Medicine medicine.disease biology.organism_classification Virology Pyrimidines Models Chemical Purines Molecular Medicine Cidofovir medicine.drug |
| Zdroj: | Nucleosides, Nucleotides & Nucleic Acids. 24:331-341 |
| ISSN: | 1532-2335 1525-7770 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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