Email:  Lab Location: Neuros #06-04/05  Tel: 64074223

Our team is focused on the development of synthetic peptides as tools for accelerating therapeutic lead discovery. In this process, peptides function as a ‘stepping stone’ from therapeutic targets to small molecule drug leads, by facilitating the discovery and structural characterization of ‘ligandable’ sites on a target surface.

As a unique approach to ligand discovery, we build on recent advances in affinity selection – mass spectrometry, which facilitate the discovery of ligands from synthetic peptide libraries. We aim to develop this approach in three general directions:

As a complimentary approach to in-vitro selection, for discovery of binding molecules (e.g., peptide macrocycles)
To examine libraries containing a high proportion of non-proteogenic amino acids, and to engage ‘cryptic’ binding pockets (e.g. by covalent ‘tethering’)    
To select for properties beyond binding affinity (e.g., passive membrane permeability)

We are also interested in using peptide ligands directly as tool compounds, in conjunction with emerging approaches for intracellular delivery. The ubiquitin proteasome system is an area of special interest.

Zak’s role within the DITL Team draws on his expertise with solid phase synthesis1, bioorganic chemistry2, and synthetic peptide libraries3-5. Our work is carried out collaboratively with the Institute of Chemical and Engineering Sciences, where Zak is jointly appointed.

Selected references:
1. Gates ZP, Dhayalan B, Kent SBH (2016) Obviation of hydrogen fluoride in Boc chemistry solid phase peptide synthesis of peptide-αthioesters. Chem Commun. 52(97):13979–13982
2. Dunkelmann DL, Hirata Y, Totaro KA, Cohen DT, Zhang C, Gates ZP, Pentelute BL (2018) Amide-forming chemical ligation via O-acyl hydroxamic acids. Proc Natl Acad Sci USA. 115(15):3752–3757
3. Gates ZP, Vinogradov AA, Quartararo AJ, Bandyopadhyay A, Choo Z, Evans ED, Halloran KH, Mijalis AJ, Mong SK, Simon MD, Standley EA, Styduhar ED, Tasker SZ, Touti F, Weber JM, Wilson JL, Jamison TF, Pentelute BL (2018) Xenoprotein engineering via synthetic libraries. Proc Natl Acad Sci USA. 115(23): E5298–E5306
4. Touti F, Gates ZP, Bandyopdhyay A, Lautrette G, Pentelute BL (2019) In-solution enrichment identifies peptide inhibitors of protein–protein interactions. Nat Chem Biol. 15(4): 410-418
5. Quartararo AJ, Gates ZP, Somsen BA, Hartrampf N, Ye X, Shimada A, Kajihara Y, Ottmann C, Pentelute BL (2020) Ultra-large chemical libraries for the discovery of high-affinity peptide binders. Nat Commun. 11:3183