Pyrophosphate analogues

Bisphosphonates (BP) are today the first line treatment of benign and malignant bone diseases. As pyrophosphate analogues (Fig. 3), BP accumulate in bone and are taken up by osteoclasts. Once in the cell, the nitrogen-containing BP (N-BP) such as Alendronate, Risedronate, Ibandronate and Zoledronate effectively inhibit osteoclast resorption and induce cell... 

Antibodies against the virus but also amantadine and derivatives, interfere with host cell penetration. There are nucleoside analogues such as aciclovir and ganciclovir, which interfere with DNA synthesis, especially of herpes viruses. Others like zidovudine and didanosine, inhibit reverse transcriptase of retroviruses. Recently a number of non-nucleoside reverse transcriptase inhibitors was developed for the treatment of HIV infections. Foscarnet, a pyrophosphate analogue, inhibits both reverse transcriptase and DNA synthesis. Protease inhibitors, also developed for the treatment of HIV infections, are active during the fifth step of virus replication. They prevent viral replication by inhibiting the activity of HIV-1 protease, an enzyme used by the viruses to cleave nascent proteins for final assembly of new vi-rons. 

Foscarnet sodium is an pyrophosphate analogue. It inhibits viral DNA polymerase and reverse transcriptase. Its main indication is cytomegalovirus retinitis in AIDS patients which have contraindications for ganciclovir. 

Foscarnet is an inorganic pyrophosphate analogue which causes selective inhibition of viral DNA polymerase and reverse transcriptase. Topical foscarnet cream has appeared to be a safe and effective treatment for aciclovir-unresponsive mucocutaneous herpes simplex virus infection in AIDS patients. 

Foscamet (Foscavir) is an inorganic pyrophosphate analogue that acts in vitro against HSV-1, HSV-2, VZV, CMV, EB V HBV, and HIV. It acts as a noncompetitive inhibitor of viral DNA polymerase and reverse transcriptase by reversibly binding to the pyrophosphate-binding site of the viral enzyme and preventing the cleavage of pyrophosphate from deoxynucleoside triphosphates. 

L D. The conversion of penciclovir to its active form requires initial monophosphorylation by viral thymidine kinases, then conversion to its active triphosphate form by cellular enzymes. Thus, the concentration of penciclovir triphosphate is particularly high in cells infected with its target viruses (e.g., HSV, VZV, HBV). Foscarnet is a pyrophosphate analogue that does not require activation. Oseltamivir is a neuraminidase inhibitor that is con-... 

Cohen, L.H., et al. (1999). Inhibition of human smooth muscle cell proliferation by farnesyl pyrophosphate analogues, inhibitors of in vitro protein farnesyl transferase. Biochem Pharmacol 57 365-373. 

Holstein, S.A., Wohlford-Lenane, C.L., Wiemer, D.F., and Hohl, R.J. (2003). Isoprenoid pyrophosphate analogues regulate expression of Ras-related proteins. Biochemistry 42 4384 391. 

The resulting pyrophoric potassium salt is of interest since it contains an aza-analogue of the phosphate anion. Further, this salt may be converted into a pyrophosphate analogue, formulated as K6[(HN)2(N=)PNHP(=N)(NH)2], in liquid ammonia. 

The second intravenous agent approved for the treatment of CMV retinitis was foscarnet. Foscarnet (trisodium phosphoformate) is a synthetic, water-soluble pyrophosphate analogue that inhibits replication of herpesviruses in vitro (3,14). It noncompetitively binds to the exchange site of viral DNA polymerase, thereby... 

Other pyrophosphate analogues containing the a-ketophosphonic function that have been tested against the HIV-1 reverse transcriptase (RT) include oxophosphonacetic acid (COPAA) and oxomethanebisphosphonic acid (COMBP). These compounds have been found to be significantly less active against RT than PFA COMBP has also been shown to inhibit mammalian DNA polymerases selectively. ... 

Naryshkin, N.A., Farrow, MJV., Ivanovskaya, M.G., Oretskaya, T.S., Shabarova, Z.A., and Gait, M.. (1997) Chemical cross-linking of the human immunodefidency virus type 1 Tat protein to synthetic models of the RNA recognition sequence TAR containing site-spedfic trisubstituted pyrophosphate analogues. Biochemistry, 36 (12), 3496-3505. 

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