Oleg Melnyk
Protein total synthesis

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Oleg Melnyk’s lab

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The team develops innovative approaches in protein chemistry and biosystems design, in the study of signaling pathways using various cellular and animal models and above all in developing novel therapeutic strategies against Schistosomiasis through integrated chemical biology programs.
The team is particularly active in developping novel methodologies for protein chemical synthesis. The first discovery which is now considered as a significant advance in the field of peptide and protein total synthesis is SEA ligation and derived methodologies (Fig. 1A).

Figure 1. A) SEA and SeEA ligations. B) K1 dimers act as potent in vivo agonists.
SEA ligation is a chemoselective reaction that leads to the formation of a peptide bond to cysteine residue between two unprotected peptide segments, i.e. a peptide featuring a SEA group at the C-terminus and an N-terminal cysteinyl peptide. This reaction has been patented and licensed to two companies in 2013. One of these companies is the start-up XProChem, which was co-founded by two former members of CBC team and O. Melnyk in Sept 2012. More recently, we introduced several concepts that facilitate considerably the access to sophisticated peptide scaffolds or large proteins. In particular, the SEA on/off concept allows triggering of the reactivity of the SEA group by controlling the reducing power of the reaction mixture. [1] Alternately, the SEA on/off concept allows the synthesis of cyclic or branched peptides that are promising scaffolds for improving the potency and stability of bioactive peptides and thus designing future peptide therapeutics. [2] Very recently, we introduced the selenium version of SEA ligation (SeEA ligation), which in combination with SEA chemistry extends our capacity to access complex polypeptides. [3]
Our capacity to access modified protein domains enabled us to investigate the role of N and K1 domains of HGF/SF in the binding and activation of MET RTK. This led to the discovery of the key role played by the multivalent display of K1 domain in the activation of MET receptor [4] and in the design of strong MET binders and agonists in collaboration with the group of Ermanno Gherardi (University of Pavia, Italy). These agonists were patented in 2015 and are currently developed for therapeutic applications in regenerative medicine with the financial support of SATT Nord (Fig. 1B).

[1a. Boll, E.; Drobecq, H.; Ollivier, N.; Blanpain, A.; Raibaut, L.; Desmet, R.; Vicogne, J.; Melnyk, O., Nat. Protoc. 2015, 10, 269-292.
b. Ollivier, N.; Vicogne, J.; Vallin, A.; Drobecq, H.; Desmet, R.; El-Mahdi, O.; Leclercq, B.; Goormachtigh, G.; Fafeur, V.; Melnyk, O., Angew. Chem. Int. Ed. 2012, 51, 209-213.

[2a. Boll, E.; Drobecq, H.; Lissy, E.; Cantrelle, F. X.; Melnyk, O., Org. Lett. 2016, 18, 3842-3845.
b. Boll, E.; Dheur, J.; Drobecq, H.; Melnyk, O., Org. Lett. 2012, 14, 2222-2225.

[3a. Raibaut, L.; Cargoet, M.; Ollivier, N.; Chang, Y. M.; Drobecq, H.; Boll, E.; Desmet, R.; Monbaliu, J.-C. M.; Melnyk, O., Chem. Sci. 2016, 7, 2657-2665
b. Raibaut, L.; Drobecq, H.; Melnyk, O., Org. Lett. 2015, 17, 3636-9.

[4Simonneau, C.; Berenice, L.; Mougel, A.; Adriaenssens, E.; Paquet, C.; Raibaut, L.; Ollivier, N.; Drobecq, H.; Marcoux, J.; Cianferani, S.; Tulasne, D.; de Jonge, H.; Melnyk, O.; Vicogne, J., Chem. Sci. 2015, 6, 2110-2121.