Date of Award

Spring 3-2000


© 2000 Ian Paquette

Document Type




First Advisor

William P. Malachowsky


Serine proteases are a large family of proteolytic enzymes which utilize a serine residue as a reactive nucleophile in the active site. Some of the more common serine proteases are chymotrypsin, trypsin, thrombin, human leukocyte elastase (HLE), human cathepsin G, and human cytomegalovirus protease (HCMV protease). Unregulated serine protease activity has been implicated in several common ailments, including rheumatoid arthritis, emphysema, pancreatitis, atherosclerosis, cystic fibrosis, and Alzheimer’s disease. Since serine proteases are responsible for the onset of such a wide range of diseases, there is an equivalent need for a large library of synthetic serine protease inhibitors to selectively counteract these conditions. To date, several serine protease inhibitors have been developed with reactive functionality. Additionally, compounds which have incorporated the monocyclic b-lactam into their structure have also been reported to inhibit some serine proteases. To date, all reported monocyclic b-lactam inhibitors take advantage of the reactivity of the b-lactam ring, however, none of the previously synthesized inhibitors attempt to deliberately mimic the natural substrates of serine proteases. The inhibitors proposed in this project will incorporate the reactive b-lactam functionality into the peptide backbone of a serine protease substrate. Molecules will be synthesized and tested in an inhibition assay with chymotrypsin, the prototypical serine protease. These monocyclic b-lactam inhibitors will theoretically be recognized by the serine protease as a substrate, and bind in a manner which places the b-lactam at the active site. These inhibitors have been rationally designed to inhibit serine proteases by this mechanism, however, previous research involving b-lactam type inhibitors of serine proteases,has shown that inhibitors sharing the same functionality often behave differently in enzyme assays. Because of this, the exact mode of inhibition of these compounds will need to be determined experimentally. If these rationally designed compounds are found to successfully inhibit chymotrypsin, the library of reactive functionality that can be used to combat serine protease activity will be expanded. Unlike many of their predecessors, these inhibitors will have the distinction of being able to exploit interactions with the enzyme on both sides of the scissile bond.


Honors Thesis.*

*Ian's was the first student honors thesis presented at UNE. A medical biology major who minored in mathematics, Ian completed his honors thesis research with the UNE chemistry department, and presented his thesis to UNE chemistry and physics faculty.

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