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Structure-Guided Design of Novel Therapeutics Targeting Translesion DNA Synthesis and Lipid A Biosynthesis

dc.contributor.advisor Zhou, Pei Najeeb, Javaria 2019-06-07T19:48:10Z 2021-05-21T08:17:11Z 2019
dc.description Dissertation
dc.description.abstract <p>Cancer is one of the most devastating diseases in modern society, with over 1.6 million new cancer cases occurring in the US alone each year. DNA-damaging agents are often the first line of defense against rapidly dividing cancer cells. However, cancer cells can become resistant to chemotherapy by up-regulating an error-prone DNA-repair process called translesion DNA synthesis (TLS). The Rev1 polymerase orchestrates this pathway by recruiting one of three inserter polymerases and the extender polymerase (Pol ζ) to bypass the lesion. Here we report the discovery and characterization of an inhibitor of the protein-protein interaction between Rev1 and Rev7, a subunit of Pol ζ, using biochemical and biophysical techniques. Our X-ray crystallographic structural analysis of the Rev1 and the inhibitor (JH-RE-06) complex reveals that the inhibitor blocks Rev7 binding by inducing Rev1 dimerization. Such an unexpected observation is confirmed by an in vitro crosslinking assay. In vitro cell-killing assays show that JH-RE-06 enhances sensitivity of a variety of cancer cell lines to a wide range of chemotherapeutic agents; furthermore, co-administration of JH-RE-06 with cisplatin significantly suppresses melanoma growth in mice and prolongs the survival time of tumor bearing mice, highlighting the therapeutic potential of translesion synthesis inhibitors as a novel class of cancer adjuvant therapeutics to enhance the outcome of chemotherapy currently available to cancer patients.</p><p>Due to their compromised immune systems, cancer patients are particularly susceptible to opportunistic bacterial infections, many of which are becoming rapidly resistant to current antibiotic therapies. We describe the combined use of X-ray crystallography and NMR spectroscopy to delineate a cryptic inhibitor envelope for optimization of a small molecule inhibitor of LpxC, an enzyme essential to the survival of Gram-negative bacteria. The resulting inhibitor shows vast improvement over its parent compound over a wide range of bacterial orthologs. </p><p>In summary, we demonstrate successful structural characterization and structure-guided design and optimization of lead compounds in two different systems. These studies have profound implications for drug discovery and lead optimization in other disease-relevant systems as well.</p>
dc.subject Biochemistry
dc.subject Biophysics
dc.subject Antibiotic
dc.subject Cancer Therapy
dc.subject NMR spectroscopy
dc.subject Structure-aided drug design
dc.subject X-ray crystallography
dc.title Structure-Guided Design of Novel Therapeutics Targeting Translesion DNA Synthesis and Lipid A Biosynthesis
dc.type Dissertation
dc.department Biochemistry
duke.embargo.months 23

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