Technology

Lassotides™

A new therapeutic modality that combines the benefits and overcomes the limitations of antibodies (Abs) and small molecules (SMs)

  • A vast untapped source of novel medicines has emerged from nature with the discovery of >10,000 bacterial lasso peptides.
  • High resistance to proteolytic, pH, and thermal degradation offers many advantages, including metabolic stability and no immunogenicity.
  • Extreme lasso peptide diversity is accessible for discovery. Amino acid variations are introduced at key positions in the loops, rings, and tails to optimize properties.
  • These custom-engineered lasso peptides are called Lassotides™.

Target Selection and Treatment Strategies

Disease targets that are challenging for current modalities are
identified as opportunities for Lassotides™

  • Lassotides designed to work where Abs and SMs struggle
  • Targets identified as causal drivers of pathology
  • Shape and size of lassotides ideal for binding in pockets
  • Oral dosing and intracellular targets demonstrated
  • Initial focus on oncology, but targets for autoimmune
    diseases, pain, and inflammation are planned

Discovery Engine

Unveiling unique natural and designed lasso peptide diversity with
drug-like properties for treating human disease

Natural Lassos

  • Over 1 million natural scaffolds predicted
  • Gold mine of new mechanisms of action
  • Screening against targets and diseased
    cells for new activities

Engineered Lassotides™

  • In silico, structure-based lasso designs
  • Natural scaffolds serve as starting points
  • Evolution complements computation
  • Rapid production and testing methods

Platform Technlogy

Combining advanced synthetic biology, computational, evolution, and
well-designed screening methods to discover and optimize our lead Lassotides™

Proprietary Curated Database

>100,000 lasso peptide genes

Cell-Free Biosynthesis (CFB)

Rapid production of novel lassotides directly from genes

Performance by Design

• Computational modeling
• Binding epitope grafting
• Lassotide evolution libraries
• Non-natural amino acids

Scaling Lassotide™ Therapeutics

Using cutting-edge synthetic biological techniques combined with sophisticated fermentation methodologies, large quantities of lassotides can be manufactured.

  • The unique structure of lasso peptides can only be synthesized using biological processes
  • Drug-like lassotide therapeutics are produced using engineered organisms in fermenters
  • Industrially established host organisms are used to develop an optimized process

Optimized lasso pathway

Engineered host

Produce gms → kgs

Preclinical Development

Unveiling unique natural and designed lasso peptide diversity with
drug-like properties for treating human disease

Lassotide in vitro pharmacology

  • Affinity assays – high potency and selectivity
  • Residence time – peptides >10x SMs
  • Metabolic stability – lassotides excreted intact
  • Plasma protein binding – tunable, conjugates
  • Safety – no off-target activity or immunogenicity

Lassotide™ in vivo pharmacology

  • Pharmacokinetics – t½ > 6 h, Vz >1 L/kg
  • Pharmacodynamics – TI >10
  • Tissue distribution – >10x vs antibodies

Lasso Conjugates

  • Half-life extension
  • Cytotoxic payloads
  • Bispecific activities

Further Reading

The following papers provide details regarding the key features of lasso
peptides and the technologies we use to develop them.

Hegemann et al., Lasso Peptides: An Intriguing Class of Bacterial Natural Products (2015). Acc. Chem. Res., 48, 1909−1919. (PubMed)

Seow et al., Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists (2016). Scientific Reports, 6:24575. (PubMed)

Tietz et al., A new genome-mining tool redefines the lasso peptide biosynthetic landscape (2017). Nature Chem Bio, 13, 470-478. (PubMed)

DiCaprio. et al., Enzymatic Reconstitution and Biosynthetic Investigation of the Lasso Peptide Fusilassin (2019). J. Am. Chem. Soc., 141, 290−297.​ (PubMed)

Al Toma et al., Site-Directed and Global Incorporation of Orthogonal and Isostructural Noncanonical Amino Acids into the Ribosomal Lasso Peptide Capistruin (2015). ChemBioChem, 16, 503 –509. (PubMed)

Si et al., Cell-Free Biosynthesis to Evaluate Lasso Peptide Formation and Enzyme−Substrate Tolerance (2021). J. Am. Chem. Soc., 143, 5917−5927. (PubMed)

Lasso Peptides

A new therapeutic modality that combines the benefits and overcomes the limitations of antibodies (Abs) and small molecules (SMs)

  • A vast untapped source of novel medicines has emerged from nature with the discovery of >10,000 bacterial lasso peptides.
  • 3D arrangement of 15-25 amino acids positions side chain functionality for maximum engagement with receptors – see how they are formed.
  • High resistance to proteolytic, pH, and thermal degradation offers many advantages, including metabolic stability and no immunogenicity.
  • Extreme lasso peptide diversity is accessible for discovery through amino acid variations across scaffolds with different loop, ring, and tail sizes.

Target Selection and Treatment Strategies

Disease targets that are challenging for current modalities are
identified as opportunities for lasso peptides

  • Lassos designed to work where Abs and SMs struggle
  • Targets identified as causal drivers of pathology
  • Shape and size of lassos ideal for binding in pockets
  • Oral dosing and intracellular targets demonstrated
  • Initial focus on oncology, but targets for autoimmune
    diseases, pain, and inflammation are planned

Discovery Engine

Unveiling unique natural and designed lasso peptide diversity with
drug-like properties for treating human disease

Natural Lassos

  • Over 1 million natural scaffolds predicted
  • Gold mine of new mechanisms of action
  • Screening against targets and diseased
    cells for new activities

Designed Lassos

  • In silico, structure-based lasso design
  • Natural scaffolds serve as starting points
  • Evolution complements computation
  • Rapid production and testing methods

Platform Technlogy

Combining advanced synthetic biology, computational, evolution, and
well-designed screening methods to discover and optimize lead lassos

Proprietary Curated Database

>100,000 lasso peptide genes

Cell-Free Biosynthesis (CFB)

Rapid production of novel lassos directly
from genes

Performance by Design

• Computational modeling
• Binding epitope grafting
• Lasso evolution libraries
• Non-natural amino acids

Scaling Lasso Therapeutics

  • The unique structure of lasso peptides can only be synthesized using biological processes
  • Drug-like lasso therapeutics are produced using engineered organisms in fermenters
  • Industrially established host organisms are used to develop an optimized process

Optimized lasso pathway

Engineered host

Produce gms → kgs

Preclinical Development

Unveiling unique natural and designed lasso peptide diversity with
drug-like properties for treating human disease

Lasso in vitro pharmacology

  • Affinity assays – high potency and selectivity
  • Residence time – peptides >10x SMs
  • Metabolic stability – little lasso degradation
  • Plasma protein binding – tunable, conjugates
  • Safety – no off-target activity or immunogenicity

Lasso in vivo properties

  • Pharmacokinetics – t1/2 > 6 h, Vz >1 L/kg
  • Pharmacodynamics – TI >10
  • Tissue distribution – >10 vs antibodies

Lasso Conjugates

  • Half-life extension
  • Cytotoxic payloads
  • Bispecific activities

Further Reading

The following papers provide details regarding the key features of lasso
peptides and the technologies we use to develop them.

Hegemann et al., Lasso Peptides: An Intriguing Class of Bacterial Natural Products (2015). Acc. Chem. Res., 48,
1909−1919.

Seow et al., Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of
complement C5a antagonists (2016). Scientific Reports, 6:24575, doi:10.1038/srep24575.

Tietz et al., A new genome-mining tool redefines the lasso peptide biosynthetic landscape (2017). Nature Chem
Bio, 13, 470-478.

DiCaprio et al., Enzymatic Reconstitution and Biosynthetic Investigation of the Lasso Peptide Fusilassin
(2019), J. Am. Chem. Soc., 141, 290−297.​

Al Toma et al., Site-Directed and Global Incorporation of Orthogonal and Isostructural Noncanonical Amino Acids
into the Ribosomal Lasso Peptide Capistruin (2015). ChemBioChem, 16, 503 – 509.

Si et al., Cell-Free Biosynthesis to Evaluate Lasso Peptide Formation and Enzyme−Substrate Tolerance (2021).
J. Am. Chem. Soc., 143, 5917−5927.

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