Development of peptide inhibitors for neuroinflammation and neurodegeneration

DESCRIPTION provided by applicant The prevalence of Alzheimerandapos s disease AD is poised to increase exponentially with the growing aging population worldwide In the United States total annual costs of AD care are projected to increase from $ billion in to over $ trillion in Paucity of disease modifying therapies capable of slowing the disease progression is an acute unmet need Considerable evidence suggests that dysregulated activation of nuclear factor kappa B NF in the central nervous system CNS contributes significantly to the beta amyloid A deposition inflammation and neurodegeneration in AD The goal of biological therapies is to restore healthy balance by targeting specific molecules that promote imbalanced responses Provaidya LLC has identified an innovative strategy to selectively target activated p the NF subunit that perpetuates neuroinflammation and neurodegeneration Glucocorticoid induced leucine zipper GILZ is a NF interacting protein that binds the transactivation domain of p p TAD exposed in activated cells and suppresses activation of pathological mediators Structurally the proline rich p binding motif of GILZ adopts polyproline type II PPII helical conformation PPII helices at intermolecular interfaces behave as adaptable gloves in obtaining the correct binding orientation with the partner protein and are considered excellent drug targets In the GILZ p TAD complex the critical proline of GILZ adopts PPII helix at interface with the highly conserved phenylalanine residues in p TAD Scientists at Provaidya developed rationally designed analogs of the p binding motif of GILZ by introducing residue substitutions with increased propensity to form and stabilize PPII helix in the context of p TAD Homology modeling and docking analyses showed that select Provaidya GILZ analogs PGA exhibit structural similarity near native docking and similar binding kinetics with p TAD as wild type GILZ Functional evaluation of top PGA showed that the peptides are well tolerated with half minimal lethal dose LD comparable to known peptide drugs Two peptides PGA and PGA protected human brain cells against A induced toxicity in vitro Specific aims of this Phase I STTR proposal are to investigate the effects of PGA and PGA on cellular morphology and A production in an in vitro neurodegeneration model in which human fetal neuronal cell derived cultures exhibit differentiated neurons and proliferative glia to evaluate the therapeutic efficacy of PGA and PGA in R transgenic AD mouse model of AD that shares many characteristics of human AD and to transform efficacious PGA into small molecules Successful completion of these studies will prepare for investigational new drug evaluations of PGA Preliminary data suggest that the PGA will likely impact several aspects of AD pathology including A deposition inflammation and neuronal apoptosis Provaidya strongly believes that upon successful development PGA will have a tremendous impact on disease progression and greatly improve the quality of life in AD PUBLIC HEALTH RELEVANCE The increasing prevalence of Alzheimerandapos s disease AD and the availability of few effective therapies magnified by the increasing cost of care define the tremendous opportunities for small drug developers in AD pharmacotherapy Provaidya LLC has developed rationally designed low molecular weight peptide drugs called Provaidya GILZ analogs PGA that selectively target activated NF p a molecule intricately associated with A deposition inflammation and neurodegeneration in AD The overall goal of this STTR proposal is to evaluate the therapeutic potential of select PGA in preclinical AD models as a pre requisite for investigational new drug development and human clinical trial