Pleconaril – Is It the “Key" to Keeping Rhinovirus Locked out of Cells?

Standing in the Way of the Common Cold Pleconaril – Is it the “Key" to Keeping Rhinovirus Locked Out of Cells? MUHS SMART Team: J. Fuller, D. Kim, E. Arnhold, R. Sung, A. Borden, L. Ortega, R. Johnson, H. Albornoz-Williams, C. Gummin, A. Martinez, N. Boldt,D. Ogunkunle, P. Ahn, B. Kasten, Q. Furumo, N. Yorke, J. McBride, I. Mullooly, D. Hutt Teachers: Keith Klestinski, Carl Kaiser Mentor: William T. Jackson Ph.D., Microbiology and Molecular Genetics, Medical College of Wisconsin Abstract Virus Mechanism of Intrusion Human Rhinovirus Capsid Section Bound to Pleconaril According to World Health Organization statistics, the human common cold is the most prevalent known disease of humans. The majority of colds are caused by the human Figure 2 rhinovirus--an enterovirus genetically similar to dangerous viruses like polio and hepatitis A. Rhinovirus infection can lead to 72-hour periods of morbidity, including symptoms like sore throat, runny nose, and muscle weakness, often causing people to miss school or work. Primary model Color: Rhinovirus is inert until infection occurs causing the immune system to then combat the Figure 3 Dodger Blue virus. Rhinovirus transmission is usually via aerosolized respiratory droplets or contact Beta Sheets: Medium with contaminated surfaces. Once in the body, the virus binds to the cell surface, allowing it Spring Green to enter cells. Cells use the Intercellular Adhesion Molecule 1 (ICAM-1) signaling protein to Alpha Helix: Green latch on to each other, but most viruses bind to ICAM-1 using a site on the virus surface Yellow known as the “canyon.” Since there are over 150 rhinovirus serotypes, it is impossible to Pleconaril: put every serotype in one vaccine. Instead, scientists are developing new drugs, such as H-Bonds: Light Grey pleconaril, that bind to the canyon and prevent the virus from attaching to the host cell. This Figure 1 Struts: White then prevents the virus from replicating thus eliminating the spread of the virus and the symptoms caused by it. The Marquette University High School SMART Team modeled a portion of the human rhinovirus capsid bound to pleconaril using 3D printing technology. Rhinovirus Symptoms: sneezing, sore throat, runny nose, muscle Figure 1: The virus utilizes ICAM-1 to latch onto the cell’s surface and begins weakness, coughing, Effectiveness of Pleconaril the process to take control of the cell. and head aches in Virus Infected Mice Figure 2:The virus has bound itself to multiple ICAM-1 receptors to bring itself The data piece demonstrates the Severe cases of to the cell surface in order to inject its genetic material. effectiveness of Pleconaril in mice. It rhinovirus in early childhood are Figure 3: The virus has begun to inject its genetic material to take over the shows that 100% of the mice survived believed to be the cell and begin the process of replication. infection when they were given 75 leading cause of mg/Kg/day of pleconaril, and that the asthma Photo Courtesy: Tim Pannell/Corbis lesser doses resulted in more fatalities from the virus. Common strategies against viruses The Body Response—Antibodies that cause very different diseases The antibodies found in humans work Conclusion Polio Human Rhinovirus by attaching onto the canyon found Human rhinovirus causes a majority of the sickness found in the world. Once on the virus and preventing it from infection occurs, a 72-hour period begins, when the antibodies found in humans binding to the cell. The issue though begin to fight off the virus causing symptoms like sneezing and a runny nose. with antibodies is that they are specific to one type of virus causing a Although many viruses can be controlled through vaccination, for rhinovirus this delay from when the virus is detected is impossible because vaccines cannot protect against the over 150 ever- to the time that it is fought off. the evolving rhinovirus serotypes. This means that the multitude serotypes prevents time during the antibodies activity is researchers from creating a single vaccine forcing patients to receive hundreds also when the symptoms occur, of vaccinations. Therefore, scientists have begun to develop new drugs like because they are the bodies way of The two images on the right show the similar structures, such as the binding canyon, of the polio and pleconaril that bind to the canyon of the virus and thus preventing it from ever rhinoviruses. Understanding the less dangerous rhinovirus will allow scientist to gain a better combatting the disease. latching onto the host cell. Thus, the purpose of scientific exploration is to understanding of polio and other similar viruses. The left-hand graphic describes the surprisingly close similarity between rhinovirus and viruses that cause hepatitis, hand-foot-and-mouth disease, enteric develop new drugs that can inhibit the virus from replicating and thus eliminating distress, cardiac infections, and poliomyelitis. the spread of the virus and the symptoms caused by it. Pleconaril References Why No Vaccination? 1 Hendrik Jan Thibaut, Armando M. De Palma, Johan Neyts (2011). Combating Enterovirus There is no vaccine because it is impossible to put Replication: State-of-the-Art on Antiviral Research. Biochemical Pharmacology 82 (2012) 185- every serotype into one vaccine, forcing people to 192 receive at least 50 shots 2 Daniel C. Pevear, Tina M. Tull, Martin E. Seipel, James M. Groarke (1999). Activity of The drug Pleconaril has been developed to combat the human Pleconaril against Enteroviruses. Antimicrobial Agents and Chemotherapy 43 (1999) 2109-2115. The rhinovirus is ever evolving with new serotypes rhinovirus by blocking the binding canyon of the virus. This being discovered every year, still forcing people to mechanism works in the same way as the antibodies found in The SMART Team Program is supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant get a new shot each year in addition to the ones humans, because they both prevent the virus from ever latching Number 8UL1TR000055. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. already recieved onto the cell. .

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