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A screening strategy to identify novel immunomodulators

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thesis
posted on 08.12.2021, 08:52 by Patel, Vimal

Understanding the immunomodulatory activities of compounds is important to identify the unintended adverse immunomodulatory effects of therapeutic compounds in development and to select novel compounds that may provide benefit for those diagnosed with immunemediated disorders. In both these cases, it is desirable to identify compounds with immunomodulatory activity early in the drug discovery process in a medium-throughput format. A screening strategy has been designed to fulfil these needs.  The first step in designing the strategy was to select informative assays and optimise individual assays to suit medium-throughput drug discovery. These individual assays investigated effects on a broad range of functions associated with innate and adaptive immune cells including macrophages (activation, cytokine production, phagocytosis and motility), helper T cells (activation and cytokine production), cytotoxic T cells (degranulation and cytokine production), and B cells (antibody production and cytokine production). Cost effectiveness and ease-of-use were important considerations during assay design and optimisation.  Using a compound set comprised of positive controls (i.e. compounds known to alter specific immune functions), a data set was generated to guide the strategy design. Assays were ordered to efficiently use resources and reduce the generation of less informative data. Additionally, using data collected from this compound set, strategies to assess and identify immunomodulatory activity were built and analysed. A second set of compounds was used to validate the screening strategy, and this screen highlighted new and novel activities for these known compounds that suggests they possess additional immunomodulatory effects.  Once validated, several novel compounds were run through the screen, including a traditional Samoan medicine, a heparan sulfate mimetic, and a novel anti-cancer agent; unique immunomodulatory activities were discovered. Finally, a hierarchical cluster analysis was used to cluster compounds sharing similar activity profiles and suggested the potential to develop further statistical methods to provide insight into compound characterisation. Together, this research has developed and validated a novel, medium throughput drug discovery system that can facilitate the identification of the immunomodulatory activities of compounds in the drug discovery environment.

History

Copyright Date

01/01/2019

Date of Award

01/01/2019

Publisher

Te Herenga Waka—Victoria University of Wellington

Rights License

Author Retains Copyright

Degree Discipline

Biomedical Science

Degree Grantor

Te Herenga Waka—Victoria University of Wellington

Degree Level

Doctoral

Degree Name

Doctor of Philosophy

ANZSRC Type Of Activity code

1 PURE BASIC RESEARCH

Victoria University of Wellington Item Type

Awarded Doctoral Thesis

Language

en_NZ

Victoria University of Wellington School

School of Biological Sciences

Advisors

La Flamme, Anne; Teesdale-Spittle, Paul