Acycloguanosine，a kind of drug

Acycloguanosine is a guanosine analogue antiviral drug, marketed under trade names such as Cyclovir, Herpex, Acivir, Acivirax, Zovirax, Zoral, and Xovir. One of the most commonly used antiviral drugs, it is primarily used for the treatment of herpes simplex virus infections, as well as in the treatment of varicella zoster (chickenpox) and herpes zoster (shingles).

Acycloguanosine was seen as the start of a new era in antiviral therapy, as it is extremely selective and low in cytotoxicity. Nucleosides isolated from a Caribbean sponge, Cryptotethya crypta, were the basis for the synthesis of Acycloguanosine. It was discovered by Howard Schaffer following his work with Robert Vince, S. Bittner and S. Gurwara on the adenosine analog acycloadenosine which showed promising antiviral activity. Later, Schaffer joined Burroughs Wellcome and continued the development of Acycloguanosine with pharmacologist Gertrude B. Elion. Vince later went on to invent abacavir, an nRTI drug for HIV patients. Elion was awarded the 1988 Nobel Prize in Medicine, partly for the development of Acycloguanosine . Dr. Richard Whitley, a University of Alabama at Birmingham researcher and pioneer in antiviral therapy, was the first to successfully use the drug in humans.

Acycloguanosinediffers from previous nucleoside analogues in containing only a partial nucleoside structure: the sugar ring is replaced with an open-chain structure. It is selectively converted into acyclo-guanosine monophosphate (acyclo-GMP) by viral thymidine kinase, which is far more effective (3000 times) in phosphorylation than cellular thymidine kinase.

Subsequently, the monophosphate form is further phosphorylated into the active triphosphate form, acyclo-guanosine triphosphate (acyclo-GTP), by cellular kinases. Acyclo-GTP has approximately 100 times greater affinity for viral than cellular polymerase. As a substrate, acyclo-GTP is incorporated into viral DNA, resulting in premature chain termination. Although Acycloguanosine

resembles a nucleotide, it has no 3' end. Therefore, after its incorporation into a growing DNA strand, no further nucleotides can be added to this strand. It has also been shown that viral enzymes cannot remove acyclo-GTP from the chain, which results in inhibition of further activity of DNA polymerase. Acyclo-GTP is fairly rapidly metabolised within the cell, possibly by cellular phosphatases.

In sum, Acycloguanosine can be considered a prodrug: it is administered in an inactive (or less active) form and is metabolised into a more active species after administration.

Acycloguanosine is active against most species in the herpesvirus family. In descending order of activity:

•     Herpes simplex virus type I (HSV-1)

•     Herpes simplex virus type II (HSV-2)

•     Varicella zoster virus (VZV)

•     Epstein-Barr virus (EBV)

•     Cytomegalovirus (CMV) – least activity

Activity is predominantly against HSV, and to a lesser extent VZV. It is only of limited efficacy against EBV and CMV. It is inactive against latent viruses in nerve ganglia.

Resistance to Acycloguanosine is rare, but is more common in patients on chronic antiviral prophylaxis (transplant recipients, people with acquired immunodeficiency syndrome due to HIV infection). Mechanisms of resistance in HSV include deficient viral thymidine kinase; and mutations to viral thymidine kinase and/or DNA polymerase, altering substrate sensitivity. Acycloguanosine has also shown cross-resistance with valAcycloguanosine and famciclovir.

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