Ebola

=__Disease/Drug of interest:__ Ebola/ ZMapp =

Ebola, formerly Ebola hemorrhagic fever, is an often fatal disease caused by infection by one of the virus’ many forms in humans as well as primates [1]. While the disease itself remains relatively rare, there have been intermittent outbreaks since its discovery, most recently in 2014 [1]. To this day, researchers are not aware of the original host of the virus, though it is suspected that the virus is most probably animal born and comes from bats [1]. The disease can be contracted through direct contact, broken skin, mucous membranes, sexual contact, or the exchanging of bodily fluids such as urine, saliva, sweat, and vomit [1]. The virus itself comes from the family Filoviridae, and up till today, five species of the virus have been identified, four of which have been identified to infect humans [1].

In context of today’s society, the virus spread quietly in a small village in Guinea during late December of 2013 and wasn’t even identified by name until March of the following year [2]. It has been suspected that the virus outbreak was due to reducing forest populations which exposed humans to potentially infected bat species [2]. Symptoms include fever, muscle pains, weakness, fatigue, diarrhea, vomiting, and random hemorrhages.

Finding a potential vaccine for Ebola is extremely important because of how fast in can spread in developing nations or rural populations as was seen in the 2014 Ebola outbreak in Africa. In fact, Ebola is so contagious that doctors and healthcare workers were required to wear specialized space suits, or full body suits, that completely shielded them from exposure to infected patients [1]. In addition, because doctors and medical facilities were so ill-prepared in the beginning to handle the outbreak, the disease spread more than it should have had it been discovered before March of 2014.

The fever has 50-90% lethality and coupled with the fact that there technically isn’t a reliable vaccine or treatment makes it an important public health concern [3]. The drug described in this report, Z-Mapp, is based on a discovery made by researchers in which it was determined that the surface glycoprotein of the virus is the only part that is responsible for attacking new host cells and hiding form the body’s natural immune response. Thus, determining the crystal structure of the glycoprotein (GP) was crucial for developing a potential vaccine as explained below [3]. **Fig 1.** This map shows the sources of outbreak for the Ebola virus as well as the range of the fruit bats which are thought to have been the cause for the 2014 Ebola outbreak.

__Target Information: __
Because the Z-Mapp vaccine is still undergoing clinical trials, the mechanism of attack on the Ebola virus is not completely understood. Nonetheless, researchers have determined that Z-Mapp works by utilizing three particular antibodies including c13C6, c2G4, and c4G7 which work together against the Ebola glycoprotein [4]. The reason researchers have focused on the glycoprotein (GP) is because it has been the only virally expressed protein on the surface that is viewed to be critical for attachment to new host cells. Thus, it is of utmost importance when developing vaccines [9]. The GP is solely responsible for attachment, fusion, and targeting new cells. It is also what differentiates between different viral species of Ebola [9]. In HEK293T cells, it has also been shown, both in //in vitro// and //in vivo// that the overexpression of GP causes cytotoxicity and lesser regulation of multiple surface proteins involved in the immune response [9].

[[image:glycoprotein.png width="640" height="263"]]
**Fig 2.** These images show the crystal structure of the Ebola virus GP (glycoprotein) with the GP1 and GP2 subunits.

Size:
The mature Ebola glycoprotein consists of two disulfide-linked cleavage products. The GP1 fragment is 140 kDa while the GP2 fragment is 26 kDa [5].

Location:
The Ebola glycoprotein is usually found inside the cells of the Ebola virus.

Function in a normal cell:
The Ebola glycoprotein is not usually found in a normal cell.

__Drug Information: __
<span style="font-family: 'Times New Roman',Times,serif;">Because ZMapp is still undergoing clinical trials, the mechanism of attack on the Ebola virus is not completely understood. However, researchers have determined that ZMapp is a cocktail drug composed of three humanized monoclonal antibodies including c13C6, c2G4, and c4G7 which work together against the Ebola glycoprotein [4]. These antibodies are first made by immunizing mice where the glycoprotein is replaced with the Ebola glycoprotein that is targeted by ZMapp. The specific antibodies that bind to to this glycoprotein and thus protect the mice from infection are isolated and made to resemble human antibodies. Lastly, these antibodies are reproduced in tobacco plants [7].

<span style="font-family: 'Times New Roman',Times,serif;">Schematic figure of drug:
<span style="font-family: 'Times New Roman',Times,serif;"> <span style="font-family: 'Times New Roman',Times,serif;">**Fig 3.** This image shows the Ebola virus and the locations at which the three Z-Mapp antibodies (colored) bind to the virus.

<span style="font-family: 'Times New Roman',Times,serif;">Formula:
<span style="font-family: 'Times New Roman',Times,serif;">Not available.

<span style="font-family: 'Times New Roman',Times,serif;">Molecular weight:
<span style="font-family: 'Times New Roman',Times,serif;">Not available.

<span style="font-family: 'Times New Roman',Times,serif;">CAS Number:
<span style="font-family: 'Times New Roman',Times,serif;">Not available.

<span style="font-family: 'Times New Roman',Times,serif;">Delivery Method:
<span style="font-family: 'Times New Roman',Times,serif;">ZMapp is administered intravenously, or directly through the patient's bloodstream [7].

<span style="font-family: 'Times New Roman',Times,serif;">Side Effects:
<span style="font-family: 'Times New Roman',Times,serif;">Mapp Biopharmaceuticals has stated that because clinical trials are still in progress, nothing can be clearly stated about potential side effects [7]. However, they have noted that other monoclonal antibody therapies, which is the same approach that they have taken with ZMapp, have been approved by the FDA with "a good safety record" [7].

<span style="font-family: 'Times New Roman',Times,serif;">Other Names:
<span style="font-family: 'Times New Roman',Times,serif;">No other known names.

<span style="font-family: 'Times New Roman',Times,serif;">Maker or Company:
<span style="font-family: 'Times New Roman',Times,serif;">ZMapp was made by Mapp Biopharmaceutical [7].

<span style="font-family: 'Times New Roman',Times,serif;">Is it patented?
<span style="font-family: 'Times New Roman',Times,serif;">ZMapp is patented by Mapp Biopharmaceuticals.

<span style="font-family: 'Times New Roman',Times,serif;">Clinical Trials Info:
<span style="font-family: 'Times New Roman',Times,serif;">ZMapp is currently undergoing clinical trials but has been in Phase 2 as of October 5, 2015; however, during the time of the 2014 outbreak, it was actually used to treat numerous patients. Five of these seven patients are still alive, but there is no direct link between the drug and their discovery [6]. Currently, any decision to use ZMapp for a specific patient is a decision to be made by the attending physician under the regulations of the FDA.

<span style="font-family: 'Times New Roman',Times,serif;">Origin:
<span style="font-family: 'Times New Roman',Times,serif;">The origins of ZMapp or based on deriving the three monoclonal antibodies from mice based on using the Ebola glycoprotein to see which mice produce antibodies that are able to fight the virus as described earlier. These antibodies are then "humanized" and then produced through tobacco plants.

<span style="font-family: 'Times New Roman',Times,serif;">Alternatives to this drug:
<span style="font-family: 'Times New Roman',Times,serif;">Due to the urgency of the Ebola outbreak and because no other cure not previously existing, numerous companies jumped on the chance to develop a drug to fight Ebola. This includes TKM-100802, MIL-77 by MabWorks, BCX-4430 by Biocryst, Iterferons, Amiodarone, and FX06.

===<span style="font-family: 'Times New Roman',Times,serif;">Other uses: <span style="font-family: 'Times New Roman',Times,serif; font-size: 13px; line-height: 1.5;">Can this drug be used to treat other diseases/conditions? === <span style="font-family: 'Times New Roman',Times,serif; font-size: 13px; line-height: 1.5;">Because ZMapp is currently undergoing clinical trials for Ebola, it has not been explored or tested for any other medical diseases/ conditions.

__<span style="font-family: 'Times New Roman',Times,serif;">References: __
<span style="font-family: 'Times New Roman',Times,serif;">[1] "About Ebola Virus Disease." Centers for Disease Control and Prevention. Centers for Disease Control and Prevention, 03 Nov. 2015. Web. 06 Feb. 2016.

<span style="font-family: 'Times New Roman',Times,serif;">[2] "Origins of the 2014 Ebola Epidemic." WHO. N.p., n.d. Web. 06 Feb. 2016.

<span style="font-family: 'Times New Roman',Times,serif;">[3] "Structure of the Ebola Virus Glycoprotein Bound to an Antibody from a Human Survivor." Structure of the Ebola Virus Glycoprotein Bound to an Antibody from a Human Survivor. N.p., n.d. Web. 06 Feb. 2016.

<span style="font-family: 'Times New Roman',Times,serif;">[4] "How to Use Chimera: Ebola Virus." Ebola Structure. N.p., n.d. Web. 06 Feb. 2016.

<span style="font-family: 'Times New Roman',Times,serif;">[5] Volchkov, V. E.; Feldmann, H.; Volchkova, V. A.; Klenk, H.-D. Processing Of the Ebola Virus Glycoprotein by the Proprotein Convertase Furin. Proceedings of the National Academy of Sciences. 1998, 95, 5762–5767.

<span style="font-family: 'Times New Roman',Times,serif;">[6] ScienceDaily. ScienceDaily, n.d. Web. 06 Feb. 2016.

<span style="font-family: 'Times New Roman',Times,serif;">[7] "ZMapp™ FAQ - Mapp Biopharmaceutical, Inc." Mapp Biopharmaceutical Inc. N.p., n.d. Web. 06 Feb. 2016.

<span style="font-family: 'Times New Roman',Times,serif;">[8] 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. Journal of Virology. 2015, 89, (21), 10982–10992.

<span style="font-family: 'Times New Roman',Times,serif;">[9] Lee, Jeffrey E., and Erica Ollmann Saphire. "Ebolavirus glycoprotein structure and mechanism of entry." Future Virology. U.S. National Library of Medicine, n.d. Web. 06 Feb. 2016.

<span style="font-family: 'Times New Roman',Times,serif;">[10] 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. Proceedings of the National Academy of Sciences Proc Natl Acad Sci USA. 2014, 111, (48), 17182–17187.

__<span style="font-family: 'Times New Roman',Times,serif;">External links: __
<span style="font-family: 'Times New Roman',Times,serif;">http://mappbio.com/z-mapp/