Cathepsin C is a drug target for toxoplasmosis

• Restricted to UC San Diego use only

• 2012

• Say, Irene

Cathepsin C is a cysteine protease that is a critical mediator of growth and intracellular survival of Toxoplasma gondii, an opportunistic protozoan parasite most responsible for severe central nervous system infection found in AIDS patients (Que et al., 2007). One- third of the American population harbors latent infection of T. gondii, mainly through the consumption of undercooked meat, but most remain asymptomatic as long as immunocompetence is maintained (Jones et al., 2003; CDC, 2009). However, the parasite reactivates when cellular immunity declines, such as in organ transplant and AIDS patients, leading to a constellation of neurologic deficits and disorders (Jones et al., 2003). Identification and characterization of novel Cathepsin C inhibitors in vitro is a fundamental first step in designing better treatment for toxoplasmosis. In this study, B11, a novel inhibitor of native T. gondii Cathepsin C (TgCPC1) was analyzed by assaying its inhibition of protease activity and ability to competitively inhibit TgCPC1 in the presence of FY03, a biotinylated general Cathepsin C inhibitor. B11 was chosen for study because previous inhibitor library screening by a collaborating laboratory suggested that B11 was specific for TgCPC1 inhibition. After partial purification of native TgCPC1 from T. gondii by MonoQ Fast Protein Liquid Chromatography, the inhibition of TgCPC1 activity was measured by the cleavage of a fluorescent TgCPC1 peptide substrate after TgCPC1 incubation with B11 and by Western blot analysis of competitive inhibition. We determined that B11 exhibits substantial inhibition of native TgCPC1 and may competitively inhibit TgCPC1 in the presence of other inhibitors, meriting further study as a Cathepsin C inhibitor and potential new drug scaffold

1 online resource (17 p.)

• Academic Dissertations

• Dissertations, Academic--School of Medicine. (Discipline)--UCSD

• text

Thesis (M.D.)--University of California, San Diego, 2012

Forms part of the UCSD School of Medicine independent study projects, Class of 2012

Includes bibliographical references (p. 16-17)

• Irene Say

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2020-10-22