Document Detail

Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines.
MedLine Citation:
PMID:  16247948     Owner:  NLM     Status:  MEDLINE    
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.
Erik De Clercq; G Andrei; J Balzarini; P Leyssen; L Naesens; J Neyts; C Pannecouque; R Snoeck; C Ying; D Hocková; A Holý
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Nucleosides, nucleotides & nucleic acids     Volume:  24     ISSN:  1525-7770     ISO Abbreviation:  Nucleosides Nucleotides Nucleic Acids     Publication Date:  2005  
Date Detail:
Created Date:  2005-10-26     Completed Date:  2005-12-15     Revised Date:  2013-05-30    
Medline Journal Info:
Nlm Unique ID:  100892832     Medline TA:  Nucleosides Nucleotides Nucleic Acids     Country:  United States    
Other Details:
Languages:  eng     Pagination:  331-41     Citation Subset:  IM    
Address correspondence to Erik De Clercq, Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium.
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MeSH Terms
Adenoviridae / metabolism
Adenoviridae Infections / drug therapy
Anti-HIV Agents / chemical synthesis*,  pharmacology
Antiviral Agents / chemical synthesis*,  pharmacology
Cell Line
Cytosine / analogs & derivatives,  pharmacology
HIV Infections / drug therapy
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
Reg. No./Substance:
0/Anti-HIV Agents; 0/Antiviral Agents; 0/Organophosphonates; 0/Purines; 0/Pyrimidines; 156-81-0/2,4-diaminopyrimidine; 71-30-7/Cytosine; JIL713Q00N/cidofovir

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