Acyclovir Acycloguanosine Amino Acids Biology Essay

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Introduction

Acyclovir (also known as the chemical acycloguanosine or under the IUPAC system as 2-amino-9-((2-hydroxyethoxy)methyl)-1H-purin-6(9H)-one) is a commonly used antiviral drug with extremely selective and low cytotoxic properties. It is effective against some types of DNA viruses, including most notably, the herpes simplex virus (HSV types 1 and 2) and the varicella-zoster virus, which causes chicken-pox and shingles. It is sold in the United States under the pharmaceutical name Zovirox, administered orally as a treatment for acute herpes or varicella outbreaks, to reduce the symptoms and speed healing time of the infections, as an acute inhibitor of the viruses.

Chemical Structure

HN

N

O

H2N

N

N

O

OH

2-amino-9-((2-hydroxyethoxy)methyl)-1H-purin-6(9H)-one

(does not contain stereocenters)

2-hydroxyethoxymethyl group

Purine group

Makes this a Purinone

Amine Group

History

In 1974, antiviral drug screening research programs at Burroughs Wellcome led to the discovery of acyclovir, an acute viral inhibitor phosphorylated by the viral-induced thymidine kinase. After concerted efforts to test the drug, noting its potential to reduce the propensity for infection and virulence of common sexually transmitted diseases, the first acyclovir drug became available in 1982, as a topically-applied cream designed to heal lesions caused by the herpes and varicella viruses faster. (King 176-177) The discovery of acyclovir was truly a breakthrough in antiviral drug research, as its mechanism and structure continues to be a catalyst for research into new antiviral drugs used to treat a wide variety of other infections, including Ganicyclovir, used to treat cytomegalovirus (CMV) retinitis (a serious eye infection that can cause blindness) and the investigational integrase inhibitor, Elvitegravir. The impact of these antiviral therapy medicines is a reduced viral-load, propensity for infection and recurrence of acute symptoms for several different types of diseases â€" resulting in a higher quality of life for infected patients, and reduced infection rates among global populations.

Pharmacology, Synthesis, Importance and Mechanism of Action

The acyclovir molecule is a guanosine (nucleoside) analog antiviral medication, which causes chain-termination in viral DNA through a series of conversions based off of highly selective phosphorylation from the viral thymidine kinase. The acyclovir pro-drug is converted by a cascading series of kinase reactions (phosphotransferases) which transfer phosphate groups from higher-energy compounds within the infected cell. The acyclovir molecules replace the sugar ring with an open-chain structure, and then are converted into acyclo-guanosine monophosphate, followed by a reaction into an active triphosphate form. The result is acyclo-GTP, which serves as a strong viral DNA polymerase inhibitor (preventing/reducing the synthesis of new viral DNA in infected cells).

HN

N

O

H2N

N

N

O

O

O

O

O

P

OH

O

O

O

O

P

OH

O

O

P

OH

O

[[2-[(2-amino-6-oxo-3H-purin-9-yl)methoxy]ethoxy-hydroxy-phosphoryl]oxy-hydroxy-phosphoryl]oxyphosphonic acid

Activated Form of Acyclovir (by Viral Thymidine Kinase)

The mechanism of this reaction is fairly well understood by pharmaceutical and biological chemists. Research programs such as the one in the late 1960s-1980s laid significant foundation for the development of antiviral medications such as acyclovir, the reactions of which have been well documented. The viral thymidine kinase activation of this drug, a novel development reducing the cytotoxicity of the drug during dosage (as the drug does not interact very much with human thymidine kinase ~ thus reducing the damage caused to uninfected cells) is a common starting point for more advanced antiviral medications, such as those used in protease inhibitors in antiretroviral drugs. According to recent research, the most common method of acyclovir synthesis is the “condensation reaction of N,N'-diacetylguanine with (2-acetoxyethoxy)methyl acetate in the presence of p-toluenesulfonic acid” (Izawa and Shiragami, 315), with an approximate yield of 47%. A new approach detailed in the article by Izawa and Shiragami results in a large increase in yield (to 92%), using guanosine as a starting reactant and adding ethyl acetate and acetonitrile to the residue followed by a reduction in aqueous NaOH and subsequent neutralization. (Izawa and Shiragami, 316, eq 8).

Aside from the obvious benefits of using this antiviral drug, mild side effects have been noted, such as dry skin (primarily from topical exposure), nausea, agitation, joint pain, and general malaise. The side effects are mitigated by the fact that treatment is on an as-needed basis and only lasts for a short time (approx 5-7 days).

Why I Chose This Compound

I am very interested in viral pathology and antiviral drug interactions from a pharmaceutical standpoint. This molecule stands out as one of the first and leading bases of modern antiviral drug research, as it is the platform for many different other medications used to treat a number of viral infections, ranging in severity from influenza to HIV. Continuing research in this area, I believe, will significantly improve the quality of life for infected individuals, reduce infection rates, and may even serve to eradicate such viruses as herpes or HIV from the general population someday. Obviously, we are still far off from being able to do that, but discoveries such as acyclovir are important steps in this area of research. Millions of people have already benefited from these medications all over the world, so the impact on our daily lives from simple molecules such as acyclovir is truly remarkable.