R01AG073122

Immunoproteasome Inhibitors for the Treatment of Alzheimer's Disease - Project Summary

With the failure of nearly all clinical trials for AD drugs in the pipeline to date, identification of a new class of drug candidates has become imperative to bring about effective AD therapies. A major obstacle is the lack of promising new drug targets unrelated to the events leading to the accumulation of the amyloid-beta (Aβ) and tau-protein.

We recently reported that linear peptide epoxyketones targeting the immunoproteasome (IP), an inducible variant of the 20S constitutive proteasome (CP), may represent a new class of AD drugs that can ameliorate cognitive deficits, independently of Aβ or tau accumulation. While displaying promising efficacy, however, the prospect of these linear peptide epoxyketones for clinical use in AD appears limited at this time, due to potential issues of having poor brain accessibility, in vivo metabolic instability, and short circulation time (largely attributable to the ABCB1-mediated drug efflux at the blood-brain barrier and enzymatic hydrolysis by peptidases and epoxide hydrolases).

Yet, the family of peptide epoxyketones ('short peptides with C-terminal A',S'-epoxyketone warhead') remain attractive drug candidates considering their pharmacological advantages conferred by their proven target specificity for the proteasomes and long-term safety in the clinic. Our current findings reveal that some of the peptide epoxyketone family members containing a macrocycle have the ability to resist the ABCB1-mediated efflux and metabolic stability superior to their linear counterparts, and the potential to be a meaningful new treatment for patients with AD.

Our objective in this application is to identify and characterize one of these macrocyclic compounds best suited for brain IP inhibition in vivo and proceed to the next phase of drug development. To do this, in Aim 1 we will prepare the current sets of promising macrocyclic peptide epoxyketones with different structural features that displayed comparable target inhibition and biological activity in vitro and in cellulo on a gram scale.

In Aim 2, we will characterize in vivo properties of each macrocyclic peptide epoxyketone to identify a lead drug candidate. In Aim 3, we will verify in vivo efficacy and the proposed mechanism of action of the lead drug candidate (IP inhibition, NLRP3 inflammasome suppression of microglial IL-1α release, blockade of astrocytes transformation to A1 subtype, neuronal survival) using two mouse models of AD (APP/PS1 and PS19 tau transgenic mice).

By completing the proposed study, we will have identified a lead candidate with the best attributes for IND enabling studies and a novel mode of action. These results are expected to have an important positive impact by examining the validity of the previously untapped IP-targeting approach for AD therapy and potentially offering a new direction for AD drug discovery.

Florida International University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Miami, Florida 331992516 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 396% from $629,282 to $3,122,904.