A novel selective broad-spectrum anti-DNA virus agent

Abstract

A new compound has been found, (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine ((S)-HPMPA), that has potent and selective activity against a broad spectrum of DNA viruses, including herpes simplex virus (types 1 and 2); varicella zoster virus; thymidine kinase-deficient (TK-) mutants of herpes simplex and varicella zoster virus; human cytomegalovirus; phocid, simian, suid, bovid and equid herpesviruses; African swine fever virus; vaccinia virus; and human adenoviruses. It is also active against retroviruses. We also report that, in mice and rabbits in vivo, the compound is effective against both local and systemic infections with herpes simplex virus type 1, including herpetic keratitis caused by a TK- mutant which is resistant to the classical anti-herpes drugs.

Inhibition of Human Immunodeficiency Virus Type I Reverse Transcriptase by Suramin-related Compounds

“…Other approaches have included the use of acyclic base analogues, e.g. acyclovir which is particularly effective against herpes simplex virus (Field & Phillips, 1983), modified nucleoside analogues (De Clercq et al, 1986;Aoyama et al, 1985), pentose-modified nucleosides, e.g. 2',3'-dideoxycytosine , and the most promising agent at the moment 3'-azido-3'-deoxythymidine (AZT) Furman et al, 1986; HTLV-IIIB were harvested by low speed centrifugation at 4 °C.…”

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

“…In 2011 it will be exactly 25 years ago when we published in Nature [1] on "a novel selective broad-spectrum anti-DNA virus agent". The name of the compound, (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine [(S)-HPMPA], was not revealed in the title of the Nature paper.…”

“…Addressing these questions will open new perspectives for the clinical usefulness of these nucleotide analogues, thereby pertaining to the importance (or "magic") of the phosphonate bound. 7 therefore, does not exist of (R)-and (S)-enantiomers, were first mentioned by De Clercq et al [1]. From a mechanistic viewpoint, all acyclic nucleoside phosphonates (ANPs) need two consecutive intracellular phosphorylations, to their diphosphate form, before they can interact with their target enzyme (DNA polymerase for DNA viruses, reverse transcriptase for retroviruses) as alternate substrates (with respect to dATP, for PMEA diphosphate or (S)-…”

Novel nucleotide analogues bearing (1 H -1,2,3-triazol-4-yl)phosphonic acid moiety as inhibitors of Plasmodium and human 6-oxopurine phosphoribosyltransferases

“…Acyclic nucleoside phosphonates (ANPs) 1 represent an important class of antimetabolites that mimic the naturally occurring nucleoside monophosphates. Extensive structure-activity relationship (SAR) studies have been carried out and several distinct classes of ANPs with diverse biological activities have been identified.…”