Date of Award

11-2015

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Dermot Cox

Second Supervisor

Dr Marian Brennan

Third Supervisor

Professor Mauro Adamo

Funder/Sponsor

Science Foundation Ireland

Keywords

Molecular Medicine, Models, Molecular

Abstract

Antibodies are Y-shaped proteins that are secreted by B-cells that makes up part of the defence mechanism in the adaptive immune system. Upon infection via invading bacteria and viruses, specific antibodies are produced to target the pathogens. An antibody pathogen complex is formed and this complex interacts with its antibody receptor to be phagocytised or opsonized and is then removed from the body. IgG is one of five classes of antibodies and is the most abundant antibody found in circulation that represents over 75% of serum antibodies in the body. The IgG antibody complex can interact with cells expressing its antibody receptor inducing activation, amplification and release of pro-inflammatory cytokines that is detrimental to the body when unintended. IgG has nine receptors of which the low affinity activating receptor FcγRIIa is implicated in many autoimmune and infectious diseases. Previously within our group, based on molecular modelling of the IgG-FcγRIIa interaction, we targeted a set of residues important for the interaction via virtual high throughput screening. This yielded a set of compounds that were tested to block this interaction where the three most promising compounds were used to deduce its pharmacophore. Based on the pharmacophore, we developed 45 compounds completing a matrix of quantitative structure activity relationship on 3 generations of novel compounds. Multicomponent reactions developed within RCSI incorporating various electronic effects, sp2 bonds modifications, multiple aromatic ring substitutions and new core molecules were synthesized and tested for activity against FcγRIIa. These series exhibit a wide range of properties that inhibit direct binding of IgG to FcγRIIa via a high throughput in vitro screening assay developed by our group while also inhibiting activation of FcγRIIa through functional in vitro tests.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.

File Size

18 MB

Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2015.