Development of novel allosteric regulators of proteinase-activated receptors

Rights statement
Awarding institution
  • University of Strathclyde
Date of award
  • 2019
Thesis identifier
  • T15615
Person Identifier (Local)
  • 201571546
Qualification Level
Qualification Name
Department, School or Faculty
  • Proteinase-activated receptors (PARs), members of the G-protein coupled receptor (GPCR) superfamily of proteins, represent highly attractive targets for therapy across a wide range of diseases. Of specific interest are PAR1 and PAR2, the major signalling members of the PAR family which are associated with cardiovascular disease, cancer and inflammatory disease. However, despite significant efforts, there is only one marketed drug for the PARs available in Vorapaxar, which is used to inhibit PAR1 in the treatment of thrombosis. Thus, exploring different chemical approaches to developing better lead molecules is important to explore novel methods for modulating the PARs. Pepducins, peptidic compounds containing a palmitoyl chain, have represented a novel approach to allosteric modulation of PARs, with PZ-128 targeting PAR1 and PZ-235 targeting PAR2 as promising lead compounds. However, deviation from the general pepducin structure has not been explored and represent possible areas of improvement. Herein, 10 novel PZ-128 analogues are described as potential improvements to PZ-128 highlighting the impact of linker modification as well as cyclisation of the peptide sequence. Additionally, off-target activity of PZ-128 is also explored, highlighting some intrinsic problems with the pepducin approach. These problems were alleviated to an extent with the novel PZ-128 analogues but identifying overall improvements to the pharmacological character of the series proved challenging. Recently, two potential lead molecules were published targeting PAR2 with AZ8838 and AZ3451. These compounds have provided new insight into how we can target PAR2, allowing access to novel chemicals with improved properties. Through a series of modifications to the published chemical structures, we have accessed novel compounds that display similar biological properties to AZ8838. Herein, 15 novel analogues of AZ8838 have been synthesised and their propensity for PAR2 inhibition tested in in vitro assays, identifying one compound of comparable potency whilst exploring the SAR surrounding the AZ8838 binding pocket. Additionally, an expanded library of AZ8838 analogues has been computationally docked to assess binding within PAR2 in silico.
Advisor / supervisor
  • Plevin, Robin
  • Jamieson, Craig
Resource Type
Date Created
  • 2019
Former identifier
  • 9912922587702996