Developing Low-Density Lipoprotein Receptor-Related Protein-1 Agonists as a Therapeutic Strategy in Allergic Inflammatory Diseases
Date
2022
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Abstract
Allergic inflammatory diseases such as atopic dermatitis, eosinophilic esophagitis (EoE) and asthma are a consequence of persistent exposure to allergens leading to impaired innate immune mechanisms and dysregulated immune responses. A large unmet need exists for an effective treatment that is devoid of potentially serious side effects and without immunosuppressive effects. We have previously developed a family of first-in-class drugs derived from naturally occurring Serine Protease Inhibitors (SERPINS) that target Low-Density Lipoprotein Receptor-Related Protein-1 (LRP-1), a homeostatic receptor that regulates a multitude of critical functions of the immune response. The lead peptide, SP16, is a short (17mer) modified peptide derivative of Alpha-1 Antitrypsin (AAT). Recent work has shown that both AAT and LRP-1 play a role in alleviating allergen-driven inflammation. In this study, we have designed a series of SP16-derivative analogs modeled on the putative LRP-1 binding site, with the goal of developing these peptide therapeutics for inflammatory diseases. We have methodically screened these analogs for their ability to inhibit inflammation, refining the analog design based on structure-activity relationships. In three tissue specific cell lines, analogs showed increased potency, with dramatically improved effective concentrations (EC50s) compared to SP16, and no toxicity, thus having the potential for an increased therapeutic window. In-vitro, ELISA based LRP-1 binding assays showed target engagement. Lead analogs, screened in a rapid in-vivo mouse model of acute inflammation, exhibited significant anti-inflammatory function comparable to SP16. The analogs demonstrated improved pharmacokinetic properties and potential for a wider range of administration routes, including oral. Finally, a few select analogs, alongside SP16, were tested for their ability to inhibit TH2 mediated responses in mouse models of atopic dermatitis and asthma. Both SP16 and analogs showed significant amelioration of disease phenotypes, including thymic stromal lymphopoietin (TSLP) inhibition. Overall, the developmental work has defined two new lead SERPIN-derived LRP-1 agonists for inflammatory diseases and provided a new avenue of SP16 development in allergic inflammation.
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Keywords
Allergic Inflammation, Alpha-1 Anti-trypsin, Inflammatory disease, LRP-1, Peptide, Serpin