Antiviral potential of a new generation of acyclic nucleoside phosphonates, the 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidines.
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.
De Clercq
Erik
E
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
Andrei
G
G
Balzarini
J
J
Leyssen
P
P
Naesens
L
L
Neyts
J
J
Pannecouque
C
C
Snoeck
R
R
Ying
C
C
Hocková
D
D
Holý
A
A
D000256:Adenoviridae / Q000378:metabolism; D000257:Adenoviridae Infections / Q000188:drug therapy; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D000077404:Cidofovir; D003596:Cytosine / Q000031:analogs & derivatives / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008956:Models, Chemical; D008980:Moloney murine sarcoma virus / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis / Q000494:pharmacology; D027383:Papillomaviridae / Q000378:metabolism; D030361:Papillomavirus Infections / Q000188:drug therapy; D011212:Poxviridae / Q000378:metabolism; D011213:Poxviridae Infections / Q000188:drug therapy; D011687:Purines / Q000737:chemistry; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology*; D014615:Vaccinia / Q000188:drug therapy; D014616:Vaccinia virus / Q000378:metabolism
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D063065:Organophosphonates; D011687:Purines; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; D003596:Cytosine; D000077404:Cidofovir