Novel approaches for the directed evolution of peptide and protein therapeutics

Cibio Seminar

13 December 2019
Versione stampabile

Venue: Polo Ferrari 2, via Sommarive 9 (Povo) – Room B105
Time: 15:30 

Speaker

  • Alessandro Angelini - Department of Molecular Sciences and Nanosystems, Ca’ Foscari University & European Centre for Living Technology (ECLT)

Abstract:

Therapeutic strategies involving conventional peptides and antibodies often failed to demonstrate efficacy. Limitations of peptides include short plasma half-life, poor target binding affinities and low proteolytic stability. Failures of antibodies to achieve desired clinical outcomes have also been ascribed to their ability to bind with high affinity to only one single pathological factor although diseases usually involve multiple ligands and receptors acting in concert. To overcome these limitations, we have applied innovative in vitro directed evolution approaches for the generation and screening of very large combinatorial DNA-encoded peptide and protein libraries. By using phage display and a chemical modification reaction, we developed small and highly constrained peptides that combines multiple favorable properties such as good binding affinity, exquisite specificity, high proteolytic stability, low toxicity and good tissue penetration that make them a promising format for the development of next generation peptide therapeutics. By applying a multiple-pressure iterative combinatorial approach based on yeast surface display technology we engineered broadly crossreactive antibodies capable of simultaneously blocking multiple pathological factors providing unprecedented ability to interfere with the orchestration of intercellular communication that leads to disease. Collectively these directed evolution approaches expand our possibilities to develop novel peptides and proteins that have the potential to overcome the limitations of current therapeutics.