Conversion of Acyclic Nucleoside Phosphonates to Their Diphosphate Derivatives by 5-Phosphoribosyl-1-Pyrophosphate (PRPP) Synthetase

Abstract

Recently, we discovered a group of acyclic nucleoside phosphonate derivatives with potent and selective activity against a broad spectrum of DNA viruses (1,2). The prototype compound of this new class of compounds is (S)-9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine, designated HPMPA (Fig. 1). In these nucleoside phosphonate derivatives, the phosphorus atom is attached to the alkyl side chain of the purine base via a P-C bond. The resulting phosphonate linkage is not susceptible to hydrolysis by esterases and is chemically very stable. While HPMPA itself has poor, if any, activity against retroviruses, several other phosphonylmethoxyalkylpurine derivatives, i. e. 9-(2-phosphonylmethoxy-ethyl)adenine (PMEA), show marked antiretroviral activity. PMEA (Fig. 1) is active against viruses that belong to the herpes family and also against human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), simian immunodeficiency virus (SIV), feline immunodeficiency virus (FIV) and Moloney murine sarcoma virus (MSV) (2–9). Also, recently, a new subclass of acyclic nucleoside phosphonate derivatives, with (R,S)-9-(3-fluoro-2-phosphonylmethoxypropyl)adenine (FPMPA) as the prototype (Fig. 1), was shown to be highly selective inhibitors of retroviruses (i. e. HIV-1, HIV-2, SIV, MSV) (10,11).