Als Biopharma, Llc | Date: 2013-02-15
The present invention includes methods of generating derivatives of a protein, as well as methods of treating a subject with the derivatized proteins. More particularly, the present invention includes methods of generating derivatives of HSP 70 proteins and methods of treating a subject with the derivatized HSP 70 proteins.
Agency: Department of Health and Human Services | Branch: | Program: STTR | Phase: Phase I | Award Amount: 286.28K | Year: 2013
DESCRIPTION: We identified the Myrica cerifera (Southern Bayberry) extract using a systematic screen as a potent reducer of the structural protein tau, which accumulates in a group of diseases called the tauopathies . The most prevalent tauopathy is Alzheimer's disease, for which there is renewed interest in the identification of tau- based therapeutic approaches to treat this devastating disease; however mutations in the tau gene are the unequivocal cause of some cases of frontotemporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Few therapeutic strategies have targeted the tau protein, despite it being seen as the key factor contributing to neuronal loss in these tauopathies. In fact, depleting tau has shownpromise in ameliorating the cognitive impairment observed in mouse models in which either wild-type or mutant tau is overexpressed. Organic extraction, bioactivity-driven fractionation and nuclear magnetic resonance spectroscopy identified the cyclic diarylheptanoid myricanol as one of the main active components from Bayberry involved in lowering tau levels. A previously-uncharacterized enantiomer of myricanol [(S)-myricanol] was the predominant species produced in Myrica cerifera, and found to be primarilyresponsible for the tau lowering activity. (S)-Myricanol has no violations of the Lipinsk guidelines and, as a natural product, may be subject to active transport processes which may be useful for the oral route of administration. (S)-Myricanol representsa tractable drug candidate for both on its own as a potential therapeutic and as a novel scaffold for further structure activity relationship development. Thus, with the need for emergent anti-tau drugs to treat AD and related tauopathies we will: 1) improve the isolation of (+)-S-myricanol from Myrica cerifera, 2) develop a high-yielding and stereoselective route for the production of synthetic (S)-myricanol which will also be amenable to the preparation of novel derivatives based upon guidance from our preliminary SAR development, and 3) determine the efficacy and conduct eADME (early absorption, distribution, metabolism, and excretion) studies on (S)-myricanol and a limited subset of derivatives. The eADME studies will include metabolism in mouse and human liver microsomes, human plasma protein binding, water solubility testing, broad receptor and ion channel profiling including hERG, and initial pharmacokinetic testing in rats. We would seek to direct our program to identify agents that would be suitablefor once-daily, oral administration for the treatment of tauopathies, to increase patient compliance and penetration. We will also continue studies to characterize the mechanism of action of (S)-myricanol using a multipronged approach, taking advantage oftool and reagents that we have uniquely prepared to investigate tau biochemistry. Ultimately these studies could provide a novel series of natural-product derived tau-lowering agents as probes for pre-clinical evaluation in animal models characteristic ofthe tauopathies, and provide in vivo proof of concept validation to serve as a springboard into Phase II of the STTR program for eventual preclinical development and commercialization. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: The structural protein tau accumulates in more than 15 neurodegenerative diseases, collectively termed tauopathies , with the most common being Alzheimer's disease. Despite this fact, only one drug currently in clinical trials targets the tau protein specifically.Here, using newly identified chemical tools based our discovery of the unexpected tau lowering properties of the natural product (S)-myricanol we will explore whether the tau protein can be cleared from the brain in vivo and seek to identify drug candidates that are beneficial for the treatment of tauopathies including Alzheimer's disease.
Als Biopharma, Llc | Entity website
Senior Leadership Team The mission of ALS Biopharma, LLC is to discover new therapeutics and diagnostics that will benefit humanity, using modern methods of structural biology and ADME to derisk the drug discovery process to the greatest extent possible. Allen B ...
Cassel J.A.,Als Biopharma, Llc |
Reitz A.B.,Als Biopharma, Llc
Biochimica et Biophysica Acta - Proteins and Proteomics
Recently, it was reported that mutations in the ubiquitin-like protein ubiquilin-2 (UBQLN2) are associated with X-linked amyotrophic lateral sclerosis (ALS), and that both wild-type and mutant UBQLN2 can co-localize with aggregates of C-terminal fragments of TAR DNA binding protein (TDP-43). Here, we describe a high affinity interaction between UBQLN2 and TDP-43 and demonstrate that overexpression of both UBQLN2 and TDP-43 reduces levels of both exogenous and endogenous TDP-43 in human H4 cells. UBQLN2 bound with high affinity to both full length TDP-43 and a C-terminal TDP-43 fragment (261-414 aa) with K D values of 6.2 nM and 8.7 nM, respectively. Both DNA oligonucleotides and 4-aminoquinolines, which bind to TDP-43, also inhibited UBQLN2 binding to TDP-43 with similar rank order affinities compared to inhibition of oligonucleotide binding to TDP-43. Inhibitor characterization experiments demonstrated that the DNA oligonucleotides noncompetitively inhibited UBQLN2 binding to TDP-43, which is consistent with UBQLN2 binding to the C-terminal region of TDP-43. Interestingly, the 4-aminoquinolines were competitive inhibitors of UBQLN2 binding to TDP-43, suggesting that these compounds also bind to the C-terminal region of TDP-43. In support of the biochemical data, co-immunoprecipitation experiments demonstrated that both TDP-43 and UBQLN2 interact in human neuroglioma H4 cells. Finally, overexpression of UBQLN2 in the presence of overexpressed full length TDP-43 or C-terminal TDP-43 (170-414) dramatically lowered levels of both full length TDP-43 and C-terminal TDP-43 fragments (CTFs). Consequently, these data suggest that UBQLN2 enhances the clearance of TDP-43 and TDP-43 CTFs and therefore may play a role in the development of TDP-43 associated neurotoxicity. © 2013 Elsevier B.V. Source
Als Biopharma, Llc | Entity website
ALS typically starts with asymmetric weakness in one or more limbs, progressing to all extremities, resulting in muscle atrophy leading eventually to complete paralysis, respiratory failure, and death usually within five years. It is estimated that as many as 350,000 individuals worldwide and 30,000-40,000 in the U ...