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    
Abstract/OtherAbstract:
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
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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    
Affiliation:
Address correspondence to Erik De Clercq, Rega Institute for Medical Research, K.U.Leuven, Minderbroedersstraat 10, Leuven B-3000, Belgium. erik.declercq@rega.kuleuven.ac.be
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MeSH Terms
Descriptor/Qualifier:
Adenoviridae / metabolism
Adenoviridae Infections / drug therapy
Animals
Anti-HIV Agents / chemical synthesis*,  pharmacology
Antiviral Agents / chemical synthesis*,  pharmacology
Cell Line
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
Chemical
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

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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