Department of Biochemistry University of Oxford Department of Biochemistry
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Teaming up against cancer - Programming protein teams to induce cancer cell death

Gianluca Veggiani and members of Mark Howarth's lab have developed a solid-phase approach to synthesise protein teams that may help cancer cell killing (Veggiani et al., 2016).

Howarth Chain Graphic

Joining proteins together into multi-functional assemblies could be useful for improved diagnostic and therapeutic tools. However, it is tricky to link protein units with precise orientation. Also, if reversible bridges are used between the protein units, the assemblies can soon re-arrange or fall apart.

In 2012 Bijan Zakeri in the Howarth lab developed the SpyTag/SpyCatcher linkage system by re-engineering a protein from Streptococcus pyogenes. The approach here depended on Raphael Gayet in the lab creating a 2nd specific linkage from Streptococcus pneumoniae called SnoopTag/SnoopCatcher. Teams are formed by alternating SpyTag reaction with SnoopTag reaction on amylose resin.

The group decided to apply the new technology to synthesise controlled protein assemblies to induce cancer cell apoptosis. "Team building just involves adding and washing, with each subunit expressed in bacteria. So we could produce lots of combinations for simultaneous stimulation of Death Receptors and various different Growth Factor receptors. By screening all the combinations generated, I could find the best protein team for cell-death induction," explains Gianluca Veggiani.

Gianluca says that the polyproteams could represent a first step towards a new class of therapeutics. "There is a lot of potential in working out how to integrate signalling through multiple pathways. But our results at this stage are just a proof-of-principle in a cell-line system, so there are many interesting steps ahead," explains Mark Howarth.

References:

  1. Veggiani, G., Nakamura, T., Brenner, M.D., Gayet, R.V., Yan, J., Robinson, C.V., and Howarth, M. (2016). Programmable polyproteams built using twin peptide superglues. Proc Natl Acad Sci U S A. 2016 Feb 2;113(5):1202-7
  2. http://www.pnas.org/content/113/5/1202.long

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