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Mappalakayil , Leah

University of British Columbia

Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide and is characterized by intense itching and inflamed skin. Although the pathophysiology of AD is not entirely understood, key components of the relevant pathways have been identified as promising therapeutic targets. Specifically, thymic stromal lymphopoietin (TSLP) is a cytokine that acts as a master regulator of these T helper type 2 cell mediated inflammatory diseases. TSLP is involved in many different pathways that end with the activation of immune cells and the release of inflammatory mediators called cytokines. Current first-line treatments for AD, corticosteroids and calcineurin inhibitors, are generally effective for mild-moderate cases. Issues arise in using these treatments for chronic moderate-severe cases, like adverse effects from prolonged application as well as the necessity of systemic immunosuppressants, which are not recommended for long-term use. Therefore, there has been a recent push for novel therapeutics. Inhibition of the TSLP signalling pathway has shown therapeutic potential, establishing it as a target for the treatment of atopic diseases. Injectable monoclonal antibodies that target components of the TSLP signalling pathway have been evaluated in clinical trials, some of which have reached FDA approval while others have missed primary endpoints in phase II clinical trials. However, topical administration is favourable because of the potential for reduced systemic effects and higher treatment acceptance, highlighting the need for a topically applied treatment that targets the pathophysiology of AD. Peptide-based drugs are a growing class of therapeutics that use short amino acid chains to modulate the activity of their biological targets. One potential advantage of peptide-based therapeutics is their application as potential inhibitors of protein-protein interactions (PPIs). By designing peptides to be similar to their endogenous interacting sequence, they can serve as a starting point for the development of potent inhibitors of PPIs. Within this project, I aim to explore the druggability of the TSLP-TSLPR-Il7R𝝰 complex by designing peptides based on relevant interaction sites and assessing these peptides alongside small molecule inhibitors for their anti-inflammatory effects. The resulting lead compounds may serve as starting points for the development of novel topical therapeutics for the treatment of AD.

Text

2025-01-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86984

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/