Document Type

Thesis - Open Access

Award Date

2024

Degree Name

Master of Science (MS)

Department / School

Pharmaceutical Sciences

First Advisor

Hemachand Tummala

Abstract

Psoriasis is a long-lasting skin condition caused by the immune system, which is characterized by red, scaly areas. It mainly affects the scalp, elbows, knees, and lower back. Psoriasis, which affects around 2-3% of the world's population, has a substantial influence on the quality of life of people who suffer from it. The disorder arises due to an atypical immunological response in which the immune system mistakenly attacks skin cells, causing fast cell reproduction, inflammation, and excessive growth. Psoriasis can be treated with topical therapies, systemic drugs, and biologics. Topical therapies, including corticosteroids, vitamin D analogs, and retinoids, are commonly employed for mild to severe psoriasis but have reduced efficacy for more widespread conditions. Systemic treatments, such as methotrexate, cyclosporine, and acitretin, are employed for more severe instances but come with the potential for major adverse effects such as liver toxicity, kidney toxicity, and suppression of bone marrow function. Biologic therapies, including IL-17A inhibitors (such as secukinumab, ixekizumab, and brodalumab), have become increasingly popular. Nevertheless, they come with a high price tag and carry the potential for serious side effects, such as heightened vulnerability to infections and cancer. Moreover, a portion of patients exhibit insufficient response to existing biologics, emphasizing the necessity for novel therapeutic approaches. The objective of our research is to assess novel inhibitors of IL-17A that disrupt the dimerization and subsequent binding to its receptor. This novel strategy aims to disrupt the inflammatory process at an earlier phase. Our goal is to enhance the precision of IL-17A inhibition by focusing on the dimerization process. This could lead to a decrease in immunosuppressive effects and associated dangers. Chapter II involved the experimentation of drugs on mouse fibroblasts and human keratinocytes. At first, cell viability testing was performed on both cell lines using crystal violet and CCK-8 assays, with varying drug doses. Subsequently, their activity was tested to determine their ability to inhibit the dimerization of IL-17A. The findings demonstrated that the drugs exhibited no toxicity toward the cell lines at the specified concentration. Additionally, the IL-17A assay revealed that both drugs were capable of disrupting the dimerization of IL-17A, thereby limiting the secretion of IL-6 and IL-8. Ultimately, the selected drug was integrated into microneedles to facilitate their administration via the skin, as the stratum corneum acts as an obstacle to drug delivery. The findings from the microneedles study indicated that the drug may be efficiently administered via the skin using this technique. Overall, despite the existence of multiple therapy alternatives, psoriasis continues to be a medical illness that has substantial unresolved medical requirements. Current therapies, although successful, have significant disadvantages, such as unfavorable side effects and reduced effectiveness in certain individuals. The objective of our research was to test novel IL-17A inhibitors that disrupts cytokine dimerization, which could potentially offer a more precise and safer therapy alternative.

Library of Congress Subject Headings

Psoriasis -- Treatment.
Interleukin-17.
Autoimmune diseases.

Publisher

South Dakota State University

Download

Share

COinS
 

Rights Statement

In Copyright