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The three-dimensional structure of the recently discovered virus, known as Seneca Valley Virus-001, reveals that it is unlike any other known member of the Picornaviridae viral family (which includes the common cold viruses), and confirms its recent designation as a separate genus "Senecavirus". The new study, carried out by Vijay Reddy and colleagues Sangita Venkataraman and Jackie Loo at The Scripps Research Institute in La Jolla, California, and Seshidhar Reddy, Neeraja Idamakanti, and Paul Hallenbeck of Neotropix Inc of Malvern, Pennsylvania, shows that the viral outer protein coat resembles a craggy golf ball, with irregular dimples and protuberances. Within the shell, the viral RNA strand finds itself in a tight mesh looking like a Whiffleball. "It is not at all like other known picornaviruses that we are familiar with, including poliovirus and the rhinoviruses that cause the common cold," explains Vijay Reddy, "This crystal structure will now help us understand how Senecavirus works, and how we can take advantage of it." Senecavirus was discovered by scientists at biotech company Neotropix several years ago and was initially thought to be nothing more than a laboratory contaminant. However, the company quickly revealed it to be a pathogen, now thought to have originated in cows or pigs. Senecavirus does not infect healthy human cells, but the Neotropix researchers discovered that intriguingly it can infect certain solid tumour cells, such as small cell lung cancer, the most common form of lung cancer. This discovery raised the interesting possibility of using the virus either to kill cancer cells directly with the virus while leaving healthy tissues unaffected. Neotropix researchers have demonstrated that in laboratory and animal studies the virus demonstrates cancer-killing specificity that is 10,000 times higher than that seen with traditional chemotherapy drugs. Moreover, it has no overt toxicity. The company has thus spent some time developing the "oncolytic" virus as an anticancer agent and is currently conducting early phase clinical trials in patients with lung cancer. "SVV-001 is the first naturally occurring non-pathogenic picornavirus shown to mediate selective cytotoxicity towards tumour cells with neuroendocrine cancer features," the team says. However, an improved understanding of the viral mode of action would only come through better insights into its structure, which is where Reddy and colleagues come in. He and his Scripps Research team turned to X-ray diffraction to determine the Senecavirus crystal structure at 2.3Å resolution with support from the US National Institutes of Health. Reddy describes the differences they found between other picornaviruses and the Senecavirus as like variations among car models of the same manufacturer. "The chassis is the same, but the body style is different," he says. "How the body of a virus is shaped determines how it infects cells." The team found that the non-segmented (+)ssRNA genome of SVV-001 most closely resembles the genomes of members of the Cardiovirus group, as opposed to polio- or rhino-viruses, as previously thought, although there are important differences. "The overall tertiary structure of VP1-VP4 subunits is conserved with the exception of loops, especially those of VP1 that show large deviations relative to the members of the cardioviruses," the researchers explain. The studies hint that the surface loops of VP1 and VP2 are involved in the way the virus targets receptors on its host, the tumour cells in this case. The researchers are now conducting further investigations on this process. "It will be critically important to find out what region of its structure the virus is using to bind to tumour cells, and what those cancer cell receptors are," Reddy explains, "Then we can, hopefully, improve Senecavirus enough to become a potent agent that can be used with many different cancers." The team has, of course, added the structure of the Senecavirus to the Scripps Virus Particle Explorer. This online database represents a worldwide resource for virologists and so far contains details of 253 viruses. Reference:
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