Herpes+Simplex+Virus


 * Disease/Drug of interest: HSV/Acyclovir**


 * Motivation and Background:**

Herpes Simplex Virus (HSV) is an infectious disease present in approximately 60%-95% of adults world [1]. There are two main types of HSV that affect humans, HSV1 and HSV2 [1]. HSV1 is much more common and typically causes lesions in and around the mouth (cold sores), though it can cause infections in the eye, face, pharynx, and central nervous system [1]. HSV2 usually causes infections of the genital and anal regions, although both viruses can infect any area of the body [1]. Although most people with the Herpes virus show little to no symptoms throughout their lives, the virus can cause serious complications in infants and people with HIV [2]. Additionally, HSV-2 can cause miscarriages in infected mothers [2].

With no known vaccine and such prevalence in the general population, HSV causes much concern and anguish to many people around the world. Painful lesions, discomfort in sexual relationships, and serious complications are all possibilities when infected with HSV [2]. Because of how common and easily transmittable HSV is (e.g. receiving a kiss from an infected relative, sharing a drink with someone who has HSV1, sexual contact), and the fact that no known vaccine is available, there is a need for a drug to help alleviate some of the symptoms or to slow the spread of the disease [1]. HSV has immeasurable effects on such a large portion of the world, but because it is nearly invisible most of the time, it tends to be thrown on the back burner in terms of research. Other more fatal diseases tend get more attention because of their very evident effects, but the sheer scale of Herpes on humankind and its irreversible, agonizing effects need to be stopped. It's frankly unacceptable that a virus can have such a hold on a humans as a whole at this point in history, and with our advances in medicine it's very possible that we could have a viable vaccine by now given enough funding.


 * References/External Links:**

[1] P. Chayavichitsilp, J. Buckwalter, A. Krakowski, S. Friedlander, Herpes Simplex. Pediatrics in Review 2009, 30, (4) 119-130. [2] [] [3] A. Wagstaff, D. Faulds, K. Goa, Aciclovir, Drugs 1994, 47, (1) 153-205. [4] [] [5] [] [6] [] [7] [] [8] [] [9] [] [10][|https://pubchem.ncbi.nlm.nih.gov/compound/2022#section=Top] [11][] [12][|https://clinicaltrials.gov/ct2/show/results/NCT01281007?sect=X70156&term=HSV+and+Aciclovir&rank=36#outcome1] [13][] [14]Gnann, JW Jr, Barton, NH, Whitley, RJ, Acyclovir: mechanism of action, pharmacokinetics, safety and clinical applications. Pharmacotherapy 1983, 3, (5), 275-83. [15][] [16][] [17] Mar EC, Chiou JF, Cheng YC, Huang ES, Inhibition of cellular DNA polymerase alpha and human cytomegalovirus-induced DNA polymerase by the triphosphates of 9-(2-hydroxyethoxymethyl)guanine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine. Journal of Virology. 1985,53(3),776-780.


 * Target Information:**

Acyclovir must be phosphorylated by HSV thymidine kinase, thus acyclovir "targets" thymidine kinase by functioning as a substrate [3]. Viral thymidine kinase is an enzyme present in herpesviruses that is responsible for the phosphorylation of deoxythymidine to deoxythymidine monophosphate. Deoxythymidine monophosphate is then phosphorylated twice more into the nucleoside deoxythymidine triphosphate, where it is incorporated into the DNA in replication [3].



Approx. 41.4 kDa Coded for in HSV genetic material and found in infected cells. Human Thymidine kinase has a similar function of phosphorylating thymidine to produce deoxythymidine triphosphate, but there are differences in the specificity for thymidine; HSV thymidine kinase has less specificity and is thus more likely to phosphorylate acyclovir.
 * Size: molecular weight of the protein**
 * Location:**
 * Function in a normal cell:**


 * Drug Information:**

Acyclovir is a nucleoside analog of guanosine [6]. It is a prodrug, and must be phosphorylated by viral thymidine kinase before it becomes active [5]. Acyclovir triphosphate works by replacing guanine in DNA replication in the host cell [3, 14]. Because acyclovir triphosphate has an incomplete sugar ring and no 3’ OH group, the addition of the drug by viral DNA polymerase terminates replication [6]. Although acyclovir triphosphate could act as an inhibitor of regular cellular DNA replication, this requires higher amounts of the drug than necessary to inhibit viral replication [6]. As such, acyclovir triphosphate has very high selectivity for HSV viral DNA polymerase [3, 14]. Although Acyclovir does not cure the patient of HSV, it does reduce the symptoms (less ulcers, shorter breakout periods) in patients showing active HSV [3].


 * Schematic figure of drug:**

C8H11N5O3 [10]
 * Formula:**

225.228g/mol [10]
 * Molecular weight:**

59277-89-3 [10]
 * CAS Number:**

Topically to the skin, intravenously, orally, or topically to the eye [3,14].
 * Delivery method:**

Most common side effects are headaches and nausea, but rare cases of neurological effects and renal failure have occurred [11].
 * Side effects:**

Acivir, Cyclovir, Herpex, Acivirax(Mash-Premier), Zovirax, Zovir [9].
 * Other names:**

Mylan Inc.
 * Maker or company:**

There are many patents on formulations including acyclovir, and the drug itself is patented by the Burroughs Wellcome Company [9,16]
 * Is it patented?**

There have been numerous clinical trials conducted with acyclovir and various parameters, such as its effect on HSV infections of the central nervous system, major infections in infants, and efficacy in patients with recurrent genital herpes (HSV2) [8].
 * Clinical Trials Info:**

Acyclovir is synthesized through a complex process starting with diglyceride (DAG), which is extracted from many seed oils, primarily cottonseed oil [9, 16].
 * Origin:**

Famciclovir is also a guanosine analog but is primarily used for shingles treatment, and valacyclovir is used for the same purpose as acyclovir, but can be taken in higher doses [12]. There have been studies on efficacy of Acyclovir in treating shingles, chickenpox, and other herpesviruses with some success in shingles [8].
 * Alternatives to this drug:**
 * Other uses: can this drug be used to treat other diseases/conditions?**