Haya Jamali

Graduation Year


Date of Thesis Acceptance

Spring 5-9-2012

Major Department or Program



Marion Gotz


Proteases are enzymes that cleave peptide bonds. One such protease is the 20S proteasome, a ubiquitous complex with a threonine-containing active site. This barrel-shaped proteasome has three distinct binding activities, chymotrypsin-like, trypsin-like, and PGPH that are specific for certain substrates. Inhibition of these binding sites of the 20S proteasome confers one method of cancer therapy. This research explores the synthesis of macrocyclic bimodal inhibitors modeled after the natural product TMC-95A, which inhibits the proteasome by a hydrogen-bonding network. Our inhibitors additionally contain a functional group that reacts with the catalytic nucleophile of the enzyme. The synthetic strategy consists of preparation of a tripeptide by solid phase synthesis followed by N-terminal coupling of a non-natural phenylalanine analog, which is synthesized starting from a benzene derivative. The first of these inhibitors has been assessed via steady-state kinetics. The dissociation constant Ki was determined to be 1.6 nM for the chymotrypsin-like activity of the 20S rabbit proteasome, followed by 13 nM and 3.5 nM for the trypsin and PGPH activity, respectively. This compound successfully inhibits the proteasome, which is promising for the other inhibitors that have been synthesized but not yet evaluated.

Page Count


Subject Headings

Protease inhibitors, Bortezomib, peptidylglutamylpeptide hydrolase, Threonine, Synthesis -- TMC-95A, TMC-95A, Chemical inhibitors, Enzymes, Whitman College -- Dissertation collection 2012 -- Chemistry Department

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Public Accessible Thesis

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