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Concept Acceleration Program (CAP) Research Project RP013

Collaborating Institution: University of Texas Southwestern Medical Center (UTSW), Dallas, TX

Principal Investigator: Beth Levine, MD

Title of the Project: An Autophagy-inducing Peptide as a Novel Therapeutic for Intracellular NIAID Class A, B, and C Priority Pathogens

Collaborators:

Expected Product: Identify novel and potent broad-spectrum antimicrobial agents.

Description: The autophagic delivery of intracellular pathogens to the lysosome (where they are destroyed) is emerging as a central mechanism of innate immunity; accordingly, the augmentation of host autophagy represents a potentially powerful new therapeutic approach to combat intracellular pathogens. The overall aim of this proposal is to facilitate the preclinical development of an autophagy-inducing peptide (or derivative thereof) for the treatment of viruses and intracellular bacteria that are on the list of NIAID Emerging and Re-emerging Diseases. To do this, the specific aims of our project are: (1) to perform preclinical evaluation of the Tat-Beclin 1 peptide by developing an assay to measure the peptide concentration in biological samples, using the assay to perform pharmacokinetic and pharmacodynamic studies in mice, determining whether the peptide is immunogenic in mice; and evaluating the toxicity of the peptide by histopathological survey of mouse organs; (2) to further evaluate the mechanism by which the Tat-Beclin 1 peptide induces autophagy as a means of potentially developing a small molecule compound with similar activity and more favorable pharmacological properties; and (3) to further evaluate the antimicrobial activity of the Tat-Beclin 1 peptide in tissue culture and mouse models of selected NIAID priority pathogens, such as West Nile virus, chikungunya virus, Rickettsia species, and Mycobacterium tuberculosis. These studies will help advance the development of a biologically active peptide (or small molecule compound that mimics its action) for the treatment of NIAID priority intracellular pathogens.