HPMPC, antiviral activity

Alternative antiviral agents for the treatment of drug-resistant herpesviruses are the acyclic nucleoside phosphonate analogs. The lead compound of this new series of antiviral molecules is cidofovir [(S)-l-(3-hydroxy-2-phosphonylmethoxypropyljcytosine] (HPMPC), which has a broad-spectrum antiviral activity in vitro and in vivo against several DNA viruses. Cidofovir has been approved for the treatment of CMV retinitis in AIDS patients, and it has also been shown to be effective in the treatment of persistent mucocutaneous infections caused by ACVr HSV and ACVr/PFAr HSV (6,7). 

Zakharova VM, Serpi M, Krylov IS, Peterson LW, Breitenbach JM, Borysko KZ, Drach JC, Collins M, Hilfinger JM, Kashemirov BA et al (2011) Tyrosine-based l-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]cytosine and -adenine ((S)-HPMPC and (S)-HPMPA) prodmgs synthesis, stability, antiviral activity, and in vivo transport smdies. J Med Chem 54 5680-5693... 

Liposomal encapsulation has the potential not only to increase the activity and prolong the residence of the drag in the eye, but also to reduce the intraocular toxicity of certain potent drags such as antimetabolites, antivirals and antibiotics to the retina. For example, liposome-encapsulated amphotericin B produced less toxicity than the commercial amphotericin B solution when injected intravitreally. Liposomes have also been used to study the release and distribution of dyes, which in turn reflect the integrity of the retinal vascular constitution. Direct intravitreal injection of liposomal-encapsulated drags has shown enhanced vitreal levels for extended periods of time in the vitreous of rabbit models. Liposomal encapsulation of the antiviral, HPMPC, reduces the toxic effects to the retina and provides therapeutic levels against CMV retinitis for up to 8 months. 

Cyclic 3, 5 -phosphates of ara-A (7, B = adenyl) [12], ara-C (7, B = cytosyl) [15] and thioinosine (8, R = H) have been synthesized [16]. The acylated thioinosine derivative (8, R = Me(CH2)i4CO, ECso 6 //M) has been shown to readily enter S49 mouse lymphoma cells and then be metabolized to thioinosine 5 -monophosphate catalyzed by phosphodiesterase and deacylation. More recently, the cyclic phosphonate analogue (9) of the antiviral (5)-l-(3-hydroxy-2-phosphonylmethoxypropyl)cytosine (HPMPC) has been prepared and shown to have comparable activity against HSV-2, both in vitro in MA-104 and MRC-5 cells and in vivo in a mouse encephalitis model, to that of the parent drug [17]. The cyclic phosphonate (9) was converted to HPMPC inside the cells, before phosphorylation to the active diphosphate. 

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