Bicycle Therapeutics Plc · NASDAQ:BCYC
Bicycle Therapeutics — ESCMID 2022
18 slides from Bicycle Therapeutics's conference presentation, October 2022
Slide 1: Characterisation of novel, non-covalent cyclic peptide (Bicycles) inhibitors of PBP3s
Characterisation of novel, non- covalent cyclic peptide (Bicycles®) inhibitors of PBP3s from important Gram-negative pathogens ESCMID 2022 Hector Newman
Slide 2: Forward-looking statements
Forward-looking statements This presentation may contain forward-looking statements made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These statements may be identified by words such as “aims,” “anticipates,” “believes,” “could,” “estimates,” “expec
Slide 3: Bicycle Therapeutics
Bicycle Therapeutics • Drug discovery and development Biopharma • Unique potential therapeutic modality - platform with potential applications across all therapeutic areas • Five molecules in clinic 3
Slide 4: Bicycles: a potential new therapeutic modality
Bicycles: a potential new therapeutic modality 1 2 Cyclise Select PoC in 6wks Optimized lead in 9m 3 Amplify • Highly constrained: high affinity, exquisite selectivity, excellent stability • Large binding footprint: disrupt protein-protein interactions • Fully synthetic: NCE classification and synth
Slide 5: Natural Product Cyclic Peptides
Natural Product Cyclic Peptides ⯇Cyclic Peptide Natural Products Challenging synthesis and optimisation Vancomycin Polymyxin Daptomycin 5
Slide 6: A platform for bi-cyclic (Bicycle) peptide discovery
A platform for bi-cyclic (Bicycle®) peptide discovery ⯇Cyclic Peptide Natural Products Challenging synthesis and optimisation Vancomycin Polymyxin Bicycles ▶ ▪Target based discovery ▪Huge diversity (>1020) ▪Chemically synthesised ▪Established pathway to optimise affinity and pharmacokinetics Daptomy
Slide 7: Penicillin binding proteins (PBPs) in bacterial cell wall synthesis
Penicillin binding proteins (PBPs) in bacterial cell wall synthesis • Assemble peptidoglycan in cell walls – multiple classes with varying function • E. coli PBP3 is an essential transpeptidase specific for cell division • Non-β-lactam PBP inhibitors would be highly desirable β-lactam PBP3 ` β-lacta
Slide 8: A promising antimicrobial Bicycle against EcPBP3
A promising antimicrobial Bicycle® against EcPBP3 TATA Porin A C S F P K C PWV E G C A ` ` PBP3 PBP3 Fluorescence polarisation (mP) 200 Periplasm Periplasm 150 GKCW101 GKCW102 MIC (µg/ml) 100 Compound E. coli E. coli GKCW101 GKCW102 (WT)* (Ec-Pore)* 50 Fluorescent Conjugate Kd 4.1 ± 0.7nM Bicycle >
Slide 9: Insights from crystallography of EcPBP3 in complex with Bicycle
Insights from crystallography of EcPBP3 in complex with Bicycle • Co-crystal structure with transpeptidase domain solved at 1.5Å • Bicycle® binds in the active site cleft • Key interactions via Phe2 and Trp6, whilst substitutions for stability were tolerated at Ser1, Lys4 9
Slide 10: Bicycle-vector tandems can cross the outer membrane barrier
Bicycle -vector tandems can cross the outer membrane barrier ® Model using periplasm entry assay (SLALOM – pep86 Split Luciferase Assay for Live monitoring of Outer Membrane transit) hv 11S ` ` pSLALOM cytoplasm Antimicrobial peptides (AMPs) offer a starting point for vector sequences • Potential ve
Slide 11: SLALOM assay identifies potential vector peptides for Bicycles
SLALOM assay identifies potential vector peptides for Bicycles T7 pep86 (v5) DRAMP (KFF)3K 18563 (v1) (v10) K F F K F F K F F K Good et al. (2001) Nature Biotechnology N A G S L L S G W G Li et al. (2018) Appl Environ Microbiol. K S L R R V W R S WW Shi et al. (2022) Nucleic Acids Research Encouragi
Slide 12: Whole-cell activity of conjugates is driven by the Bicycle
Whole-cell activity of conjugates is driven by the Bicycle® MIC (µg/ml) E. coli E. coli E. coli E. coli K. Bicycle® Vector Hemolysis GKCW101 GKCW102 ATCC ATCC BAA- pneumoniae (WT) (EcPore) 25922 2469 ATCC 43816 1 Parent Bicycle® none >128 0.5 - 2 >16 NT NT NT 2 Parent Bicycle® Vector RI 0.5 0.5 1-2
Slide 13: Whole-cell activity of conjugates is driven by the Bicycle
Whole-cell activity of conjugates is driven by the Bicycle® MIC (µg/ml) E. coli E. coli E. coli E. coli K. Bicycle® Vector Hemolysis GKCW101 GKCW102 ATCC ATCC BAA- pneumoniae (WT) (EcPore) 25922 2469 ATCC 43816 1 Parent Bicycle® none >128 0.5 - 2 >16 NT NT NT 2 Parent Bicycle® Vector RI 0.5 0.5 1-2
Slide 14: Whole-cell activity of conjugates is driven by the Bicycle
Whole-cell activity of conjugates is driven by the Bicycle® MIC (µg/ml) E. coli E. coli E. coli E. coli K. Bicycle® Vector Hemolysis GKCW101 GKCW102 ATCC ATCC BAA- pneumoniae (WT) (EcPore) 25922 2469 ATCC 43816 1 Parent Bicycle® none >128 0.5 - 2 >16 NT NT NT 2 Parent Bicycle® Vector RI 0.5 0.5 1-2
Slide 15: Promising spectrum of activity against Enterobacterales
Promising spectrum of activity against Enterobacterales % sequence homology Organism Conjugate MIC (µg/mL) of ftsI* with E. coli Enterobacterales 4-32 Escherichia coli 100 (n=4 including one NDM-1 producer) 4-8 Citrobacter freundii 96 (n=2 including one meropenem resistant) 4-8 Klebsiella pneumoniae
Slide 16: PBP inhibitors discovered using a modified phage display platform
PBP inhibitors discovered using a modified phage display platform The Bicycle discovery platform offers unique opportunities for novel antimicrobials, and is readily applicable to other targets E. coli PBP3 is highly tractable to the Bicycle platform, with low nanomolar binders identified in phage s
Slide 17: Acknowledgments
Acknowledgments Mike Skynner Steve Stanway Mike Dawson Anusha Regupathy Catherine Rowland Nik Bournakas Paul Beswick Kasia Dzionek Rachel Dods Katerine Van Rietschoten Liuhong Chem Matthew Balmforth Prof. Chris Dowson Prof. David Roper Dr. Adrian Lloyd James Wagstaff former MRC Doctoral Training Fel
Slide 18: Thank you
Thank you Bicycle Therapeutics, Inc. Bicycle Therapeutics plc 4 Hartwell Place Portway Building Lexington, MA Granta Park 02421-3122 Cambridge CB21 6GS T. +44 (0)1223 261503 Bicycle RD Limited BicycleTx Limited Portway Building Portway Building Granta Park Granta Park Cambridge CB21 6GS Cambridge CB