HaloTag protein is a kind of monomer protein with molecular weight of 33 KDa. It does not have catalytic ability, but is a genetic modified derivative of proteolytic enzyme. It can form effective covalent binding with a variety of HaloTag ligands, including TMR with red fluorescence, diacfam with green fluorescence, coumarin with blue fluorescence, biotin, etc.
Small molecule induced protein degradation is an attractive strategy for the development of chemical probes. One way to induce targeted protein degradation involves the use of PROTAC, a heterobifunctional molecule that can recruit specific E3 ligases to the desired target protein. A novel PROTAC was designed to degrade HaloTag fusion protein with VHL ligand. These HaloPROTACs will stimulate the development of PROTACs with more drug like properties. In addition, these HaloPROTACs are useful chemical genetic tools.
HaloPROTAC system uses HaloTag protein to covalently conjugate chloroalkane labeled molecules with the target fusion protein. It has been reported that HaloPROTAC recruited by VHL and CIAP can induce the degradation of various HaloTag fusion substrates. They include cytoplasmic proteins (ERK, MEK and GFP), endosomal proteins (vps34 and sgk3) and nuclear localization proteins (CREB1). HaloPROTAC also provides insights into the biology of multiple systems.
In order to use PROTAC system, it is necessary to develop PROTAC that can target the protein from scratch or modify the latter with tags to degrade the target protein by HaloPROTAC. Indeed, prior to the development of PROTAC targeting endogenous proteins, it may be advantageous to conduct preliminary studies with labeled target proteins to establish a proof of concept. In view of the latest progress in genome editing, it is relatively easy to label target proteins at endogenous sites so that they can undergo ligand induced degradation without overexpression or development of new ligands. Obviously, the workflow starts with selecting the target protein to degrade.
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