Ebola.

=__ Disease/Drug of interest: Ebola/ZMapp™ __=

**Motivation and Background** :
Ebola came into global spotlight in March of 2014 when an outbreak in West Africa was confirmed by the World Health Organization [1]. It quickly became the largest Ebola outbreak in history, resulting in a total of 28,652 total cases and 11,325 deaths as of April 13, 2016 [2]. This event had helped the rare disease gain public attention and knowledge, as well as resulted in worldwide worry about its spread as the mortality rate increased.

Ebola, also known as Ebola hemorrhagic fever, is a rare and deadly zoonic disease, which affects both humans and animals. The people who are most susceptible to the disease include healthcare workers, family or people close to the infected patient, and mourners who have direct contact with bodies [1]. Symptoms include sudden fever, intense weakness, muscle pain, headache, and sore throat in the “dry phase”, beginning, of the disease [1]. In the “wet phase”, people start vomiting, having diarrhea, rash, impaired kidney and liver function, some cases internal and external bleeding as well [1]. Treatment typically involve supportive care, monitoring fluids, kidney dialysis, blood transfusions, and plasma replace therapy [1]. This is because there is no current drug therapy effective against Ebola virus [1].

Figure 1: Infographic summarizing Ebola virus disease

=__ Target Information: Ebola Virus Envelope Glycoprotein __= The glycoprotein is a type I transmembrane glycoprotein that comprises of 676 amino acids [3]. It is also a chalice-shaped trimer, a molecule consists of three identical monomers [4]. The monomer is actually a heterodimer comprising of GP1 and GP2 [5].



Figure 2: The ebola virus. The glycoproteins are shown on the surface. 450 kDa, or 7.4724251e-16 grams On the surface of the virion
 * Size ** :
 * Location ** :

** Function in a normal cell ** :
Attaching to host cells and catalyzing membrane fusion. This is especially important for the Ebola virion since it's the only viral protein on the virion surface.

=__ Drug Information: ZMapp™ __= ZMapp is a cocktail combining three different monoclonal antibodies,c2G4, c4G7, and c13C6, that is used to prevent Ebola's spread in the body [6]. It has no other names. Not much is known yet about ZMapp, including the schematic figure, formula, or molecular weight.

Figure 3: Single particle EM reconstruction of glycoprotein ectodomains in complex with ZMapp cocktail.

1653957-71-1 It is injected intravenously, targeting the surface glycoprotein of Ebola [6]. It was developed in a group effort by scientists from the Public Health Agency of Canada, Defyrus, the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), Kentucky BioProcessing, and Mapp Biopharmaceutical, and other institutions [6]. It’s currently trademarked, not patented, by Mapp Biopharmaceutical, Inc. and LeafBio [6]. ZMapp currently has two active clinical studies. “Putative Investigational Therapeutics in the Treatment of Patients With Known Ebola Infection” was started in February of 2015, and is still ongoing [8]. “Safety and Pharmacokinetics of a Single ZMapp™ Administration in Healthy Adult Volunteers”, a Phase 1 clinical trial, is currently recruiting volunteers [8]. Because this Phase 1 trial has not been completed, the side effects of ZMapp are still unknown.
 * CAS Number ** :
 * Delivery method ** :
 * Maker or company ** :
 * Is it patented ** ?
 * Clinical Trials Info ** :

__** Origin ** : __ The three antibodies are produced by growing them in an Australian strain of tobacco that can be easily manipulated with recombinant DNA techniques [7]. The antibody genes are placed into tobacco plants in a process called agroinfiltration, where a solution of the recombinant agrobacterium is inserted into the plant’s genetic information [7]. The different monoclonal antibodies originate from two other well-known and studied anti-EBOV cocktails, ZMAb and MB-003 [4]. Together, the two cocktails contain six isolated monoclonal antibodies (MAbs) by immunization of mice, MAbs c2G4, c4G7, c1H3, c13C6, c6D8, and c13F6 [4]. The six monoclonal antibodies were tested in various combinations to find the most potent combination [4]. As a result of optimization, c2G4, c4G7, and c13C6 were combined to create the more effective ZMapp™ [4]. Several vaccines are currently undergoing clinical trials, and the treatment of convalescent whole blood and plasma transfusions are being used as an investigational therapy [10]. There are also many drugs, new and repurposed in clinical trials to test their efficacy towards Ebola. Some of the novel drugs, such as FX06 and ZMAb, have shown promise and been used compassionately on few patients [10]. A famous study from the New England Journal of Medicine, PREVAIL II (Partnership for Research on Ebola Virus in Liberia II) was published in October of 2016 [9]. It was designed by the National Institute of Allergy and Infectious Diseases (NIAID) in partnership with Ministries of Health in Liberia, Sierra Leone, and Guinea, as well as the Republic of Sierra Leone Armed Forces and INSERM (French National Institute of Health and Medical Research) [9]. 72 patients were enrolled in the adaptive randomized, controlled trial design [9]. The results showed that patients who received the drug had a 22% fatality rate while patients who received the standard Ebola care had a 37% fatality rate [9]. The study concluded that while ZMapp appeared to have beneficial effects, the results did not meet the statistical threshold for drug efficacy [9]. This drug has no known other uses.
 * Alternatives to this drug ** :
 * Miscellaneous ** :
 * Other uses ** :

**External links:**
For more information visit

http://www.mayoclinic.org/diseases-conditions/ebola-virus/basics/definition/con-20031241


 * References: **

[1] Frequently asked questions on Ebola virus disease http://www.who.int/csr/disease/ebola/faq-ebola/en/ (accessed Feb 5, 2017).

[2] About Ebola Virus Disease https://www.cdc.gov/vhf/ebola/about.html (accessed Feb 5, 2017).

[3] Volchkov, V. E.; Feldmann, H.; Volchkova, V. A.; Klenk, H. D., Processing of the Ebola virus glycoprotein by the proprotein convertase furin. Proc Natl Acad Sci U S A 1998, 95 (10), 5762-7.

[4] Davidson, E.; Bryan, C.; Fong, R. H.; Barnes, T.; Pfaff, J. M.; Mabila, M.; Rucker, J. B.; Doranz, B. J., Mechanism of Binding to Ebola Virus Glycoprotein by the ZMapp, ZMAb, and MB-003 Cocktail Antibodies. J Virol 2015, 89 (21), 10982-92.

[5] Lee, J. E.; Saphire, E. O., Ebolavirus glycoprotein structure and mechanism of entry. Future Virol 2009, 4 (6), 621-635.

[6] ZMapp™ FAQ http://mappbio.com/zmapp-faq/ (accessed Feb 5, 2017).

[7] Kroll, D. Ebola 'Secret Serum': Small Biopharma, The Army, And Big Tobacco http://www.forbes.com/sites/davidkroll/2014/08/05/ebola-secret-serum-small-biopharma-the-army-and-big-tobacco/#23c0bf2826e2 (accessed Feb 5, 2017).

[8] Search Results https://clinicaltrials.gov/ct2/results?term=zmapp&pg=1 (accessed Feb 5, 2017).

[9] Davey, R. T.; Dodd, L.; Proschan, M. A.; Neaton, J.; Neuhaus Nordwall, J.; Koopmeiners, J. S.; Beigel, J.; Tierney, J.; Lane, H. C.; Fauci, A. S.; Massaquoi, M. B. F.; Sahr, F.; Malvy, D.; Group, P. I. W.; Team, M.-N. P. I. S., A Randomized, Controlled Trial of ZMapp for Ebola Virus Infection. N Engl J Med 2016, 375 (15), 1448-1456.

[10]Ebola vaccines, therapies, and diagnostics http://www.who.int/medicines/emp_ebola_q_as/en/ (accessed Feb 5, 2017).

[11] Murin, C. D.; Fusco, M. L.; Bornholdt, Z. A.; Qiu, X.; Olinger, G. G.; Zeitlin, L.; Kobinger, G. P.; Ward, A. B.; Saphire, E. O., Structures of protective antibodies reveal sites of vulnerability on Ebola virus. Proc Natl Acad Sci U S A 2014, 111 (48), 17182-7.

[12] ViralZone: Ebolavirus http://viralzone.expasy.org/all_by_species/207.html (accessed Feb 5, 2017).