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Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines.
Nucleosides Nucleotides Nucleic Acids. 2005; 24(5-7):331-41.NN

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+Show Affiliations

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.beNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16247948

Citation

De Clercq, Erik, et al. "Antiviral Potential of a New Generation of Acyclic Nucleoside Phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines." Nucleosides, Nucleotides & Nucleic Acids, vol. 24, no. 5-7, 2005, pp. 331-41.
De Clercq E, Andrei G, Balzarini J, et al. Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines. Nucleosides Nucleotides Nucleic Acids. 2005;24(5-7):331-41.
De Clercq, E., Andrei, G., Balzarini, J., Leyssen, P., Naesens, L., Neyts, J., Pannecouque, C., Snoeck, R., Ying, C., Hocková, D., & Holý, A. (2005). Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines. Nucleosides, Nucleotides & Nucleic Acids, 24(5-7), 331-41.
De Clercq E, et al. Antiviral Potential of a New Generation of Acyclic Nucleoside Phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines. Nucleosides Nucleotides Nucleic Acids. 2005;24(5-7):331-41. PubMed PMID: 16247948.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines. AU - De Clercq,Erik, AU - Andrei,G, AU - Balzarini,J, AU - Leyssen,P, AU - Naesens,L, AU - Neyts,J, AU - Pannecouque,C, AU - Snoeck,R, AU - Ying,C, AU - Hocková,D, AU - Holý,A, PY - 2005/10/27/pubmed PY - 2005/12/16/medline PY - 2005/10/27/entrez SP - 331 EP - 41 JF - Nucleosides, nucleotides & nucleic acids JO - Nucleosides Nucleotides Nucleic Acids VL - 24 IS - 5-7 N2 - 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. SN - 1525-7770 UR - https://www.unboundmedicine.com/medline/citation/16247948/Antiviral_potential_of_a_new_generation_of_acyclic_nucleoside_phosphonates_the_6_[2__phosphonomethoxy_alkoxy]_24_diaminopyrimidines_ L2 - http://www.tandfonline.com/doi/full/10.1081/ncn-200059772 DB - PRIME DP - Unbound Medicine ER -