!Development of small molecule therapeutics against anti-infectious and anti-cancer drug resistance via structure-based drug design

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2022

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!Drug discovery typically involves structure-based drug design based on three-dimensional protein structures and hit/lead compound identification and optimization. Herein, this technique was used to overcome several obstacles associated with the developing of antibiotics, anticancer agents, and antifungals and reveal critical insights into the corresponding structure-activity relationships (SARs).Phospho-N-acetyl-muramyl-pentapeptide translocase (MraY) is an important membrane enzyme involved in the early-stage biosynthesis of bacterial peptidoglycans. As the inhibition of MraY leads to bacterial cell lysis, such MraY inhibitors (e.g., muraymycin) hold great promise for antibiotic development. However, the structural complexity of muraymycin makes its synthesis and practical applications challenging. Hence, we synthesized several muraymycin analogs with reduced structural complexity and better synthetic tractability and identified the moieties responsible for their biological activity to facilitate the development of muraymycin-derived antibiotics. Translesion synthesis (TLS) is a major mechanism that enables bypass replication over DNA lesions and promotes the formation of mutagenic DNA. Rev1/Pol ζ–mediated TLS plays an important role in cisplatin-induced mutations, and thus, the Rev1/Pol ζ interface is an attractive target for small-molecule TLS inhibitors. Herein, we aimed to develop TLS inhibitors as potential anticancer agents based on the recently reported inhibitor of the Rev1-Rev7 interaction, JH-RE-06. Despite its high potency, JH-RE-06 is poorly soluble in aqueous media and is therefore a limitation for further development. To overcome this limitation and identify novel anticancer agents, we prepared various JH-RE-06 analogs and studied the related SARs, to determine the critical functional groups for improving the biological activity improvement and aqueous solubility. Currently, fungal infections, which are particularly dangerous to immunocompromised patients, are a frequent cause of a death. However, the similarities between the eukaryotic physiologies of fungal pathogens and their hosts render targeting of the pathogen without causing side effects in the host challenging. Calcineurin (CN) plays a major role in invasive fungal diseases and is therefore a promising target for antifungal drug development. FK506, which is an approved CN inhibitor, exhibits promising activity but an insufficient selectivity because of its strong immunosuppressive effect. Therefore, in developing antifungal agents, we exploited the major structural differences between the CN-FK506-FKBP12 ternary complexes of humans and fungi and developed FK506/520 analogs targeting these complexes. The synthesized analogs retained the parent antifungal efficacy while exhibiting lower immunosuppressive activities and improved therapeutic efficacies both in vivo and in vitro.

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Lim, Won Young (2022). !Development of small molecule therapeutics against anti-infectious and anti-cancer drug resistance via structure-based drug design. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/25184.

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