Abstract
Seneca Valley Virus (SVV) is a recently discovered picornavirus that has shown promising results as an oncolytic virotherapy agent. While SVV-001 has been used in several clinical trials, other SVV clades are swine pathogens. SVV capsid structure was solved along with its interaction with its cellular receptor. An important area of research is to develop an SVV nano- vehicle for the precision delivery of chemotherapeutics. The second area of interest is developing vaccines and identifying drug targets to prevent mortality and morbidity in pigs. Picornaviruses are shown to grow in a genetic swarm or quasispecies that can quickly adapt to challenging environments. We have explored the SVV quasispecies spectra and used directed evolution to develop thermostable and pH-resistant variants of SVV, with the determination of the structural attributes for improved thermal stability.
Interactions of the virus and its receptor are an essential part of the infection equation for developing advanced therapies. The behaviour of SVV capsid proteins and its cellular receptor ANTXR1 under physiological stress is not reported before. We have examined SVV-ANTXR1 interactions in detail through long-run molecular dynamics and provided the first evidence of its dynamics in pyrexia and acidosis-like conditions.
The picornavirus genome packaging mechanism is poorly understood, which hampers the developing of novel vaccines and drug targets. We have provided the first evidence of RNA packaging signals in SVV. Our results can inform us to devise a mechanism to encapsulate therapeutic loads inside SVV capsids for targeted drug delivery.
Understanding the genetic evolution of SVV in a tumour environment is essential to identify characteristics that can be used to improve tumour regression. We have provided the first evidence of the genetic adaptability of SVV in tumour spheres and cell monolayers.
This thesis has investigated SVV capsid stability and utilised directed evolution to develop thermostable and pH-resistant mutants. Provided first evidence of RNA packaging signals in SVV, interrogated SVV capsid proteins and ANTXR1 molecular dynamics and tracked evolutionary development of SVV in tumorspheres.