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We are pleased to open registration for the next PPSG webinar held at 1 pm (UK time) on 5^th June 2026.听

The next scientists presenting will be Dr King Hang Aaron Lau (University of Strathclyde) 补苍诲听

Dr Shenaz Allyjaun听(Bicycle Therapeutics and Newcastle University)

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Dr King Hang Aaron Lau

Senior Lecturer,

Department of Pure and Applied Chemistry, University of Strathclyde

鈥�Self-Assembly of Peptoids: from Conformational Flexibility to Interfacial Crystallization and Stem Cell Differentiation鈥�

Peptoids differ from natural peptides only by a one-atom shift of the functional sidechain attachment to the nitrogen atoms along the peptide backbone. This minor change however confers the ability to access both cis and trans backbone torsions, and enables a convenient synthetic protocol that even researchers with little chemistry experience may exploit to access 250+ diverse sidechains for composing functional sequences. The Lau group has been exploring the fundamentals of peptoid self-assembly and their potential in biomedicine and therapeutics. Starting from 鈥渕inimal鈥� di- and tri-peptoids, we have shown the first examples of self-assembled peptoid nanofibers and vesicles in water. With computational chemists, we have also developed molecular dynamics simulations to study these systems. By comparing similar tripeptoids, it was found that long-range ordering correlates well with a sequence鈥檚 ability to sample its conformation space. Extending the study to monomer crystallization, we further showed that ordering can be underpinned by sidechain dynamic freedom to enable hydrophobic and ionic molecular interfaces, which may be relevant in stabilizing the assembly of peptoid nanosheets composed of longer sequences. Recent experiments have shown that the stiffness exhibited by these nanosheets can induce mesenchymal stem cell differentiation into a bone-like lineage.

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Dr Shenaz Allyjaun

Postdoctoral Research Scientist at Bicycle Therapeutics and Newcastle University

听鈥淗igh Throughput Identification and Characterization of LptDE- binding Bicycle Peptides using Phage Display and Cryo-EM鈥�

Antibiotic resistance is an increasingly prominent and widespread challenge to public health; this has prompted urgent calls for the development of new antimicrobial agents displaying innovative chemotypes and mechanisms of action (1,2). Gram-negative bacteria pose an exceptional threat, with the presence of an asymmetric outer membrane (OM) containing a protective layer of lipopolysaccharides (LPS) serving as a permeation barrier for many existing antimicrobial compounds (3). LPS biogenesis and transport systems are essential in most Gram-negative bacteria, with the OM-spanning complex LptDE being responsible for the final stages of LPS delivery to the outer leaflet of the OM (4). As an externally accessible and essential protein, LptDE offers a promising target for inhibitor development, without the need for cellular penetration. LptDE's therapeutic potential has been validated with Murepavadin, a specific and potent inhibitor of Pseudomonas aeruginosa LptDE. However, to date there are no direct inhibitors of E. coli LptDE and drug discovery is made challenging since LptDE is a membrane protein without a conventional active site (5,6). Here (7), the Bicycle phage display platform is used in combination with cryo-electron microscopy (cryo-EM) and surface plasmon resonance (SPR) to identify and map bi-cyclic peptide binders to LptDE. Bicyclic molecules can occupy chemical space that could be considered analogous to naturally occurring antimicrobials, with the added benefit of being fully chemically tuneable, allowing them to be optimised as therapeutics. Multiple high affinity (>1uM) Bicycle peptide binders were identified as LptDE-specific binders and were subsequently sorted into multiple competition 'bins' by SPR. Specific binding locations and modes were described by cryo-EM, with a data collection strategy optimised for multiple high-resolution (>3脜) LptDE-Bicycle molecule model generations per 24 hours. Structures for 8 molecules binding LptDE at 4 separate epitopes are presented, with efficient classification of binding peptides into motif-specific families. Ultimately, this methodology represents a robust screening cascade for LptDE that identifies and efficiently prioritises and classifies LptDE binding molecules of interest and rapidly localises binding sites across the protein. Given the high level of current interest in outer membrane targets from both prokaryotic and eukaryotic organisms, this workflow represents a widely applicable technique which will assist drug discovery scientists in the early identification and classification of potential hit molecules, thereby acting as an efficient early-stage triage that allows the identification and de-selection of non-functional binding sites on challenging membrane proteins.

听References:

Laxminarayan, R. The Overlooked Pandemic of Antimicrobial Resistance. Lancet 2022, 399 (10325), 606鈥� 607, DOI: 10.1016/S0140-6736(22)00087-3

Miethke, M. et al. Towards the Sustainable Discovery and Development of New Antibiotics. Nat. Rev. Chem. 2021, 5 (10), 726鈥� 749, DOI: 10.1038/s41570-021-00313-1

Nikaido, H. Prevention of Drug Access to Bacterial Targets: Permeability Barriers and Active Efflux. Science 1994, 264 (5157), 382鈥� 388, DOI: 10.1126/science.8153625

Okuda, S. et al. Lipopolysaccharide Transport and Assembly at the Outer Membrane: The PEZ Model. Nat. Rev. Microbiol 2016, 14 (6), 337鈥� 345, DOI: 10.1038/nrmicro.2016.25

Storek, K. M. et al. Massive Antibody Discovery Used to Probe Structure鈥揊unction Relationships of the Essential Outer Membrane Protein LptD. eLife 2019, 8, e46258 DOI: 10.7554/eLife.46258

Martin-Loeches, I. et al. Murepavadin: A New Antibiotic Class in the Pipeline. Expert Review of Anti-infective Therapy 2018, 16 (4), 259鈥� 268, DOI: 10.1080/14787210.2018.1441024

Allyjaun, S. et al. High-Throughput Identification and Characterization of LptDE-Binding Bicycle Peptides Using Phage Display and Cryo-EM. Journal of Medicinal Chemistry 2025, DOI: 10.1021/acs.jmedchem.5c00307