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

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 Cu^I-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 N^α-Fmoc-Xaa(ω-N₃)-OH and N^α-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, the featured speaker 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.

Speaker

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

After completing an international PhD in 1990, under the supervision of Prof. Luis Moroder of the Max Planck Institut fuer Biochemie, A.M., Papini was appointed Professor of Bioorganic Chemistry in 2002. Since 2014, she has been Director of the Research Unit PeptLab@UNIFI associating the Departments of Chemistry & NEUROFARBA, Section of Pharmaceutical Sciences at the University of Florence in Italy, and of the joined platform PeptLab@UCP at the Université Paris-Seine (France) that she contributed to founding in 2001 and 2013 respectively.

In 2008, she was awarded with the L. Zervas of the European Peptide Society and 1st D. Theodoropoulos of the Hellenic Peptide Society. In 2009, for her work in technology transfer she received, the Frost & Sullivan Excellence in Research Award in European autoimmune disease diagnostics market & Vespucci Award of Regione Toscana for the perspectives of development of the company aimed towards R&D of peptide-based diagnostics for autoimmune diseases.

Papini has been Laureate of the “Chaire d’Excellence” (2009-2014) of the French ANR, and in 2019, she was awarded the Rita Levi Montalcini Prize for binational Israeli-Italian cooperation for their common research project aimed at the role of aberrant modifications on peptide antigens in autoimmunity. From 2011-2020, she was nominated an EPS Executive Committee member acting as treasurer, and for 2019-2025 she has been elected APS Councilor. Since 2013, she has been a delegate of the International Affairs and Erasmus Program of the School of Sciences of the University of Florence. She is the Co-Founder of the first spin-off of the University of Florence EspiKem Srl, launched in 2003, the start-up Toscana Biomarkers Srl (2007-2014).

In 2017, she founded and now acts as Scientific Coordinator of PeptFarm joining PeptLab@UNIFI and Fabbrica Italiana Sintetici (FIS, Italy) to develop a large-scale synthesis of peptide drugs in the new Facility MoD&LS, incubated in the Centre of Competences of the University of Florence. Her main research interests are in glycopeptides and proteins for chemical immunology studies and in any aberrant modification triggering the immune system and developing antibodies. She has always been strongly involved in translational research projects in cooperation with clinicians, with a special attention to possible industrial applications, more recently in cosmeceutics.

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