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Obtaining Complex Peptides Thanks to Efficient Technologies is No Longer a Dream: Successful Stories of Difficult Syntheses

Prof. Anna Maria Papini, University of Florence

Prof. Anna Maria Papini,
University of Florence, Department of Chemistry "Ugo Schiff",
Interdepartmental Research Unit of Peptide and Protein Chemistry and Biology

An increasing number of peptides are used in active pharmaceutical ingredients, cosmetics, diagnostics and vaccines. Several are based on long sequences, cyclic structures and multi-branched systems that require complex synthetic strategies to incorporate homodetic and heterodetic bridges, post-translational modifications or constrained unnatural amino acids.

Therefore, peptide organic synthetic chemists have to overcome a variety of difficulties not only at small scale but also during the scale up. For example, side chain-to-side chain cyclizations represent a strategy for enrichment of bioactive conformational ensembles. Structural rigidification reduces entropy and may lock molecules into receptor binding conformations. Structural manipulations, therefore, contribute to the enhancement of target specificity, induce higher binding affinity and biological potency and often lead to lower metabolic susceptibility and more favorable pharmacokinetics.

The CuI-catalyzed azide−alkyne 1,3-dipolar Huisgen’s cycloaddition (CuAAC) provides convenient and versatile access to cyclic peptidomimetics following the incorporation of the building blocks Nα-Fmoc-Xaa(ω-N3)-OH and Nα-Fmoc-Yaa(ω-yl)-OH. The proteolytic stable side chain-to-side chain bridging [1,2,3]-triazolyl moiety in peptides, is isosteric with the peptide bond and can function as a surrogate of the classical lactam bridge.

In this webinar, Prof. Anna Maria Papini, will discuss the syntheses of biologically relevant cyclopeptides containing not only 1,4-disubstituted-[1,2,3]-triazolyl bridges but also interlocked dicarba bridges and 1,3-butadiyne constraints. This offers a powerful approach for generating stable helix mimetic structures or β-turn conformations. Not only is the stapling moiety fundamental to mimicking biological activity but also the bridge size and its location and orientation within the bridge.

These approaches have been successfully used to replace the lactam bridge and the susceptible disulfide bridge but require efficient technologies to perform on resin ring-closing metathesis, CuAAC, 1,3-butadiyne formation via the Glaser oxidative coupling.

The technology of available automated instrumentation can assist solid-phase strategies by increasing reproducibility and saving time. In addition, different mixing and heating strategies can boost reaction rates, but must be carefully managed to limit possible side-product formation typical in the syntheses of difficult sequences.

Join this webinar to hear the speaker explore multiple parameters in technologies that improve the efficacy of solid-phase syntheses in complex peptides. The role of temperature, solvent volumes, coupling systems and mixing modes (N2 bubbling and/or oscillation mixing) will be discussed, in addition and how they can optimize protocols to develop the best conditions for the small scale and mainly further upscaling of solid-phase synthesis.




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