Antiviral Potential of a New Generation of Acyclic Nucleoside Phosphonates, the 6-[2-(Phosphonomethoxy)alkoxy]-2,4-Diaminopyrimidines

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.

Mechanism of Antiviral Drug Resistance of Vaccinia Virus: Identification of Residues in the Viral DNA Polymerase Conferring Differential Resistance to Antipoxvirus Drugs

“…Due to the fact that the aliphatic phosphonate chain is linked to C-6 (and not to N-1) of the pyrimidine ring (Fig. 1), this group of pyrimidine ANPs may mimic an incomplete purine ring system (4,18).…”

“…Following the success of these drugs, two new classes of ANPs that are often referred to as "second-generation" and "third-generation" ANPs have been described. The second generation of these compounds includes the open-ring or Olinked ANPs [containing 6-(2-phosphonomethoxyalkoxy)-2,4-diaminopyrimidines] and target a broad range of DNA viruses and retroviruses (4,18,30). Two examples of these secondgeneration compounds are (R)-HPMPO-DAPy and 6-[2-(phosphonomethoxy)ethoxy]-2,4-diaminopyrimidine] (PMEODAPy) (Fig.…”

Activities of Several Classes of Acyclic Nucleoside Phosphonates against Camelpox Virus Replication in Different Cell Culture Models

“…Recently, two new classes of ANPs have been described: 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidine (DAPy) derivatives, which are considered to be the second class of ANPs, and a third class of ANPs, including HPMP derivatives with a 5-azacytosine moiety (4,16,24,28; M. Krečmerová, A. Holý, R. Pohl, M. Masojídková, G. Andrei, L. Naesens, J. Neyts, J. Balzarini, E. De Clercq, and R. Snoeck, submitted for publication).…”

The clinical potential of the acyclic (and cyclic) nucleoside phosphonates. The magic of the phosphonate bond

“…This class of compounds ( Fig. 7) could actually be divided in two subclasses: first (i), the (R)-HPMPODAPy derivatives, which akin to (S)-HPMPC, showed activity against herpes-, adeno-, poxand papillomaviruses, and, second (ii), the PMEO-DAPy, 5-X-PMEO-DAPy and (R)-PMPODAPy derivatives which, akin to PMEA and (R)-PMPA, showed activity against retroviruses (HIV-1, HIV-2) and hepadnaviruses (HBV) [50]. The activity of (R)-HPMPO-DAPy against poxviruses (i.e.…”