Chicken+Pox

=__Disease/Drug of interest:__ Chickenpox/Acyclovir =

__Motivation and Background: __
Chickenpox occurs all around the globe and was reported to affect four million people annually before the use of the varicella vaccine became widespread. The adoption of universal vaccination against varicella in 1995 reduced the incidence of varicella. Currently, fewer than ten deaths occur per year, most of them in unimmunized people. The varicella vaccine has yielded a large decrease in the number of cases and complications from the disease. Centers for Disease Control and Prevention recommend routine immunization of children at the ages of 12 to 15 months and again at ages 4 to 6. Two doses of the vaccine are approximately 98 percent effective at preventing chickenpox. Chickenpox most commonly occurs in children ten years of age or younger and is not very prevalent in adults. Most people contract the infection when they are young however, adults who have never contracted the disease before are still at risk. The virus can easily spread to people who have never been vaccinated or from people with chickenpox to others who have never had the disease. The main methods of transmission are by touching or breathing in the virus particles that come from chickenpox blisters, and possibly tiny droplets from infected people that get into the air they breathe. Symptoms of this disease appear in three stages. It starts out with an itchy rash which then turns into fluid filled blisters that eventually turn into scabs. The blisters then become scabs and ending up scabbing over. In addition to itchy bumps and scabs, chickenpox can cause fever, headache, fatigue, and loss of appetite.

__**References: **__
> Polish consensus guidelines on the use of acyclovir in the treatment and prevention of VZV and HSV infections. E. Journal of Infection and Chemotherapy 2016, 22 (2), 65–71.
 * Szenborn, L.; Kraszewska-Głomba, B.; Jackowska, T.; Duszczyk, E.; Majda-Stanisławska, E.; Marczyńska, M.; Ołdak, E.; Pawłowska, M.; Służewski, W.; Wysocki, J.; Stryczyńska-Kazubska, J.; Kuchar,
 *  Zeifman, A. A.; Novikov, F. N.; Stroylov, V. S.; Stroganov, O. V.; Chilov, G. G.; Skoblov, A. Y.; Miroshnikov, A. I.; Skoblov, Y. S. 2,3-Dihydroxy-quinoxaline induces ATPase activity of Herpes Simplex Virus thymidine kinase. FEBS Letters 2013, 588 (3), 509–511.
 * Goh, C.-L.; Khoo, L. A retrospective study on the clinical outcome of herpes zoster in patients treated with acyclovir or valaciclovir vs. patients not treated with antiviral. International Journal of Dermatology 1998, 37 (7), 544–546.

__External links: __
=__Target Information: __= An antiviral medication used to treat chickenpox has a mechanism that targets DNA polymerase and thymidine kinase in order to inhibit the disease. After conversion in vivo to the active metabolite acyclovir triphosphate by viral thymidine kinase, acyclovir competitively inhibits viral DNA polymerase by incorporating into the growing viral DNA chain and terminating further polymerization. Cells that are virally infected absorb more acyclovir compared to normal cells, therefore these cells convert more of it to the active form and the antiviral activity is prolonged. Acyclovir’s affinity for the enzyme thymidine kinase affects the inhibitory activity of the drug. Compared to varicella zoster virus, herpes simplex has a more efficient phosphorylation of the viral thymidine and therefore acyclovir has a greater antiviral activity against this disease.
 * https://pubchem.ncbi.nlm.nih.gov/compound/2022
 * https://aidsinfo.nih.gov/drugs/8/acyclovir/0/professional
 * https://www.clinicaltrials.gov/ct2/results?term=acyclovir&cond=%22Chickenpox%22

 Figure 1: 3D structure of DNA polymerase

__**<span style="font-family: Arial,Helvetica,sans-serif;">Size: molecular weight of the protein **__
<span style="font-family: Arial,Helvetica,sans-serif;">DNA polymerase has a molecular weight of approximately 94 kilo daltons while thymidine <span style="font-family: Arial,Helvetica,sans-serif;">kinase has a molecular weight of about 25 kilo daltons. Normally, it appears in tissue as a dimer with an approximate molecular weight of 50 kilo daltons. Once activated by ATP, it becomes a tetramer with an approximate molecular weight of 100 kilo daltons. <span style="font-family: Arial,Helvetica,sans-serif;"> <span style="font-family: Arial,Helvetica,sans-serif;">Figure 2: 3D structure of a tetramer of thymidine kinase, each monomer is a different color (red, blue, green, purple)

__<span style="font-family: Arial,Helvetica,sans-serif;">Location: __
<span style="font-family: Arial,Helvetica,sans-serif;">Thymidine kinase is an enzyme found in the cytosol in anticipation for cell division. DNA polymerase is found in the nucleus of a cell.

__<span style="font-family: Arial,Helvetica,sans-serif;">Function in a normal cell: __
<span style="font-family: Arial,Helvetica,sans-serif;">Thymidine kinase catalyzes the first phosphorylation step of deoxyribonucleosides in the salvage pathway in DNA synthesis. DNA polymerase is essential to the process of DNA replication. DNA polymerase removes the RNA primers and replaces it with DNA.

__<span style="font-family: Arial,Helvetica,sans-serif;">Drug Information: __
<span style="font-family: Arial,Helvetica,sans-serif;">Acyclovir is a popular antiviral drug used to treat chickenpox and other viral infections. This drug is used to decrease pain and speed the healing of sores or blisters in people who have varicella, herpes zoster (shingles), and genital herpes. Acyclovir decreases the severity and length of these outbreaks by healing the sores faster, keeping new sores from forming, and decreasing pain and itching.

__**<span style="font-family: Arial,Helvetica,sans-serif;">Schematic figure of drug: **__
<span style="font-family: Arial,Helvetica,sans-serif;"> <span style="font-family: Arial,Helvetica,sans-serif;">Figure 3: 2D schematic molecular structure of acyclovir, nitrogens displayed as blue, oxygens displayed as red

<span style="font-family: Arial,Helvetica,sans-serif;">__Formula:__
<span style="font-family: Arial,Helvetica,sans-serif;">C8H11N5O3

<span style="font-family: Arial,Helvetica,sans-serif;">__Molecular weight:__
225.208 grams per mole

<span style="font-family: Arial,Helvetica,sans-serif;">__**CAS Number:**__
59277-89-3

__**<span style="font-family: Arial,Helvetica,sans-serif;">Delivery method: **__
<span style="font-family: Arial,Helvetica,sans-serif;">This drug comes as a tablet, capsule, and a suspension (liquid) to take by mouth. It is usually taken with or without food two to five times a day for five to ten days, starting as soon as possible after your symptoms begin. If using the liquid form of this medication, shake the bottle well before each dose.

__<span style="font-family: Arial,Helvetica,sans-serif;">Side effects: __
<span style="font-family: Arial,Helvetica,sans-serif;">Common side effects of this medication include headache, nausea, diarrhea, and vomiting. More serious side effects that may indicate an allergic reaction may be hives, rash, swelling of the face, and difficulty breathing.

__**<span style="font-family: Arial,Helvetica,sans-serif;">Other names: **__
<span style="font-family: Arial,Helvetica,sans-serif;">Acycloguanosine <span style="font-family: Arial,Helvetica,sans-serif;">Zovirax

__**<span style="font-family: Arial,Helvetica,sans-serif;">Maker or company: **__
<span style="font-family: Arial,Helvetica,sans-serif;">Manufactured by several different pharmaceutical companies including Delcor Asset Corporation and GlaxoSmithKline.

__**<span style="font-family: Arial,Helvetica,sans-serif;">Is it patented? **__
<span style="font-family: Arial,Helvetica,sans-serif;">Yes

__**<span style="font-family: Arial,Helvetica,sans-serif;">Clinical Trials Info: **__
<span style="font-family: Arial,Helvetica,sans-serif;">There are twelve clinical trials concerning the treatment of chickenpox with Acyclovir.

__**<span style="font-family: Arial,Helvetica,sans-serif;">Origin: **__
<span style="font-family: Arial,Helvetica,sans-serif;">It was originally synthesized in 1974 by Howard Schaeffer at Wellcome Research Laboratories, now GlaxoSmithKline. After his discovery, Gertrude B. Elion and her team thoroughly studied this drug and the way it worked. They found that Acyclovir remains inert until it meets the herpes virus. The discovery of this drug was first announced in 1977 and was approved by the Food and Drug Administration in 1982. It was marked under the trade name Zovirax and the original formula was a topical ointment. Three years later it became available in an oral formula.

__**<span style="font-family: Arial,Helvetica,sans-serif;">Alternatives to this drug: **__
<span style="font-family: Arial,Helvetica,sans-serif;">Valtrex (Valacyclovir) <span style="font-family: Arial,Helvetica,sans-serif;">Famciclovir (Famvir)

__**<span style="font-family: Arial,Helvetica,sans-serif;"> Other uses: **__
<span style="font-family: Arial,Helvetica,sans-serif;">Acyclovir is a synthetic analog of the purine nucleoside, guanosine, with potent antiviral activity against herpes simplex viruses type one and two, varicella-zoster virus, and other viruses of the herpesvirus family.