Proteolysis targeting chimera (PROTAC®) is a new technology that has the potential to revolutionize drug discovery. As a pioneer company in the field of preclinical drug discovery, Creative Biolabs can offer advanced ligand design services to accelerate your PROTAC® development. Based on strong expertise in PROTAC® development, we are able to help clients tackle the challenges and promote the development of your programs. Here, we are happy to introduce our ligand design service for neuro-degenerative related proteins.
Proteins play critical roles in maintaining the life of organisms. Correct protein folding controls cell health and survival. However, most proteins are inherently prone to aggregation in their misfolded or partially misfolded state and thus lead to the development of many diseases, such as neurodegenerative diseases, cancers and type 2 diabetes mellitus (T2DM).
Generally, misfolded proteins are efficiently removed by quality control systems composed of the ubiquitin (Ub)-proteasome system (UPS), chaperone-mediated autophagy (CMA) and macroautophagy. But some native and mutant proteins are resistant to proteolytic pathways and can further grow into inclusion bodies or extracellular plaques that have highly ordered fibrillar structures with elevated β-sheet content. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS).
Fig.1 Fate of cellular misfolded protein. (Bolshette, 2014)
Working in the field of PROTAC® development for years, Creative Biolabs is able to develop PROTAC® degraders against numerous neurodegenerative diseases with the ability to cross the blood-brain barrier (BBB). Moreover, our experienced scientists help our clients solve multiple challenges that occurred in PROTAC® development, including but not limited to linker design and optimization. We are confident in designing novel ligand for multiple targets based on every client’s specific requirements. The services we offer are listed as followed.
Ligand Design for Huntingtin-targeting PROTAC®
Huntington’s disease (HD) is a devastating inherited neurodegenerative disorder resulting in a diverse range of behavioral, cognitive and physical symptoms, including the renowned motor disorder, chorea. Current therapeutic strategies for HD include antisense oligonucleotides, RNA interference targeting of mRNA, and CRISPR-Cas9. Despite promising, these approaches also suffer from issues of effective blood-brain barrier penetration via oral or subcutaneous delivery. However, development in PROTAC®-based small molecule approaches for drug design in other fields brought a new avenue for researchers to explore novel therapies against HD.
Ligand Design for Tau-targeting PROTAC®
Tauopathies are a group of neurodegenerative diseases characterized by the pathological accumulation of hyper-phosphorylated tau (P-tau) protein, in the form of intracellular paired helical filaments (PHFs) or neurofibrillary tangles (NFTs), within neurons and glia of affected brain regions, leading to cell death. Targeted protein degradation approaches have expanded the landscape of druggable proteins by providing a mechanism to transform a non-functional protein binder into an effective targeted degrader.
Ligand Design for α-synuclein-targeting PROTAC®
α-synuclein (α-syn) plays a significant pathogenic role in both familial and sporadic forms of Parkinson’s disease (PD). Recently, several approaches have been used to target α-syn for PD treatment, including interference with the Prion-like spread of α-syn, reducing α-syn production, inhibition of α-syn aggregation and aggregates reduction, as well as enhancing degradation of intracellular α-syn aggregates.
Ligand Design for PSD-95-targeting PROTAC®
PSD-95 is a major element of central chemical synapses and interacts with glutamate receptors, cell adhesion molecules, and cytoskeletal elements. PSD-95-targeting PROTAC® is a bifunctional molecule that recruits PSD-95 into proximity with an E3 ubiquitin ligase to trigger target ubiquitination and subsequent proteasomal degradation. PSD-95-targeting PROTAC® has emerged as a new modality of drug discovery for PSD-95 target validation and the development of novel therapeutics for neurodegenerative diseases.
With years of experience, scientists at Creative Biolabs are pleased to offer the best ligand design service to develop a variety of PROTAC®s against any target. For more detailed information, please feel free to contact us.
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