Drug discovery: repurposin drug for antifungal treatment targeting novel pathway

• Main Author: Png, Zheng Long
• Other Authors: Miao Yansong
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2023
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/167160
• Institution: Nanyang Technological University

Fungal infections have become increasingly common in recent years, with invasive fungal infection posing a significant threat to patients who are either severely ill or are immunocompromised. There are four different classes of antifungal agent being used for the treatment of fungal infections. However, the frequent use of these drugs can lead to a rise in the emergence of antifungal resistant strains. Certain species of fungi, such as Candida auris, have been reported to be multidrug resistant. Thus, highlighting the need to develop new antifungal drugs that can either kill the fungi or prevent the formation of hyphae. The target protein of interest Spa2 acts as the scaffold protein for the formation of the polarisome complex. This polarisome complex is responsible for the recruitment and assembly of actin through the interaction with the other polarisome proteins such as Aip5 and Bni1. By targeting the Spa2 protein, we aim to disrupt its role in the formation of polarisome complex, thereby preventing the formation of hyphae. Without any hyphae structure, it would stop the progress of invasive fungal infection. From the drug screening, there were 3 hits which were found to show positive binding to the Spa2. To further characterize the 3 potential drug candidates, biophysical experiments such as Isothermal Titration Calorimetry (ITC) and in vivo studies such as hyphae inhibition assay were carried out. Results obtained showed that while there is some degree of binding to the Spa2, there are no synergistic effects on inhibition of hyphae growth.b