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ATTEC

Efficient degradation of abnormal proteins is crucial to protect the cell against proteotoxic stress. Selective targeting and disposal of such proteins usually occur in a ubiquitin-dependent manner by proteasomes and macroautophagy/autophagy. Whereas proteasomes are efficient in degrading abnormal soluble proteins, protein aggregates are typically targeted for degradation by autophagic vesicles.

Enhancing proteasomal degradation of target proteins using proteolysis-targeting chimeras (PROTAC) is a promising emerging approach, but proteasomes alone are inefficient in degrading certain large proteins or aggregates. Autophagy, an independent protein-degradation pathway, is a bulk degradation system that engulfs proteins into autophagosomes for subsequent lysosomal degradation. Autophagy is present in all eukaryotic cells, and therefore harnessing the power of autophagy to degrade certain target proteins may have the potential for drug discovery.

The compounds that interact with both the disease-causing protein and the phagophore (autophagosome precursor) protein LC3 may tether the former to phagophores for subsequent autophagic degradation. This autophagosome-tethering compound (ATTEC) concept could be applied to many disease-causing proteins to treat diseases. Now, after extensive exploration and experimentation, Creative Biolabs has established a platform centered with ATTEC and we are proud to announce our innovative platform for drug discovery.

What Is ATTEC?

ATTEC is the linker compound capable of interacting with both the disease-causing protein and phagophore protein LC3. It may target the former to phagophores for autophagic degradation, based on the fact that the autophagic protein substrates are engulfed within double-membrane phagophores where lipidated LC3 proteins are associated.

How Does It Work?

The ATTEC concept was tested in the scenario of Huntington disease (HD), a neurodegenerative disorder that is caused by the mutant HTT (mHTT) protein with an expanded polyglutamine (polyQ) stretch. These linker compounds that interact with both mHTT and LC3 may tether the molecules together to enhance the recruitment of mHTT into autophagosomes, facilitating its degradation. In addition, mHTT-LC3 linker compounds that do not interact with wild-type HTT (wtHTT) may promote allele-selective degradation of mHTT.

A schematic picture illustrating the mechanism of action of ATTEC. Fig.1 A schematic picture illustrating the mechanism of action of ATTEC.

Why ATTEC?

The ATTEC opens a new window for drug discovery, different from the PROTAC strategy and the autophagy-enhancing strategy.

  • Autophagy is present in all eukaryotic cells, and therefore harnessing the autophagy power of ATTEC to degrade certain target proteins may have the potential for drug discovery.
  • ATTEC can pass the blood-brain-barrier and significantly rescue various HD-relevant phenotypes including neuronal shrinkage and apoptosis, HD Drosophila lifespan and climbing abilities, as well as HD mouse motor-function deficits.
  • ATTEC is effective in vivo in the HD mice using intraperitoneal injections.
  • ATTEC did not influence global autophagy function and autophagosome size/numbers.
  • ATTEC can drastically reduce mutant ATXN3, another polyQ expansion protein that causes spinocerebellar ataxia 3 (SCA3).

What Do We offer?

Creative Biolabs offers full drug development and licensing services using the ATTEC platform. Our services include but not limited to:

  1. Basic ATTEC design and screening
  2. In vitro evaluation of ATTEC
  3. In vivo evaluation of ATTEC

Creative Biolabs utilizes the ATTEC platform to develop a general degradation tool by conjugating the core compound structure with other compounds interacting with specific targets. If you are interested in our services, please directly contact us and consult our technical supports for more details.

For research only, do not provide service directly to individuals.

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