Antibody; Peptide; Therapy; Small molecule; Phage display; Combinatorial chemistry; Drug development; Peptidomimetic; Protease inhibitor
Chen Shiyu, Rebollo Inmaculada Rentero, Buth Sergey A., Morales-Sanfrutos Julia, Touati Jeremy, Leiman Petr G., Heinis Christian (2013), Bicyclic Peptide Ligands Pulled out of Cysteine-Rich Peptide Libraries, in JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
, 135(17), 6562-6569.
Baeriswyl Vanessa, Calzavarini Sara, Gerschheimer Christiane, Diderich Philippe, Angelillo-Scherrer Anne, Heinis Christian (2013), Development of a Selective Peptide Macrocycle Inhibitor of Coagulation Factor XII toward the Generation of a Safe Antithrombotic Therapy, in JOURNAL OF MEDICINAL CHEMISTRY
, 56(9), 3742-3746.
Chen Shiyu, Gfeller David, Buth Sergey A., Michielin Olivier, Leiman Petr G., Heinis Christian (2013), Improving Binding Affinity and Stability of Peptide Ligands by Substituting Glycines with D-Amino Acids, in CHEMBIOCHEM
, 14(11), 1316-1322.
Rebollo Inmaculada Rentero, Angelini Alessandro, Heinis Christian (2013), Phage display libraries of differently sized bicyclic peptides, in MEDCHEMCOMM
, 4(1), 145-150.
Rebollo Inmaculada Rentero, Heinis Christian (2013), Phage selection of bicyclic peptides, in METHODS
, 60(1), 46-54.
Baeriswyl Vanessa, Heinis Christian (2013), Polycyclic Peptide Therapeutics, in CHEMMEDCHEM
, 8(3), 377-384.
Angelini Alessandro, Cendron Laura, Chen Shiyu, Touati Jeremy, Winter Greg, Zanotti Giuseppe, Heinis Christian (2012), Bicyclic peptide inhibitor reveals large contact interface with a protease target., in ACS chemical biology
, 7(5), 817-21.
Baeriswyl Vanessa, Rapley Helen, Pollaro Lisa, Stace Catherine, Teufel Dan, Walker Edward, Chen Shiyu, Winter Greg, Tite John, Heinis Christian (2012), Bicyclic peptides with optimized ring size inhibit human plasma kallikrein and its orthologues while sparing paralogous proteases., in ChemMedChem
, 7(7), 1173-6.
Angelini Alessandro, Morales-Sanfrutos Julia, Diderich Philippe, Chen Shiyu, Heinis Christian (2012), Bicyclization and Tethering to Albumin Yields Long-Acting Peptide Antagonists, in JOURNAL OF MEDICINAL CHEMISTRY
, 55(22), 10187-10197.
Angelini Alessandro, Diderich Philippe, Morales-Sanfrutos Julia, Thurnheer Sarah, Hacker David, Menin Laure, Heinis Christian (2012), Chemical macrocyclization of peptides fused to antibody fc fragments., in Bioconjugate chemistry
, 23(9), 1856-63.
Pollaro Lisa, Diderich Philippe, Angelini Alessandro, Bellotto Silvia, Wegner Hermann, Heinis Christian (2012), Measuring net protease activities in biological samples using selective peptidic inhibitors., in Analytical biochemistry
, 427(1), 18-20.
Chen Shiyu, Morales-Sanfrutos Julia, Angelini Alessandro, Cutting Brian, Heinis Christian (2012), Structurally diverse cyclisation linkers impose different backbone conformations in bicyclic peptides., in Chembiochem : a European journal of chemical biology
, 13(7), 1032-8.
Heinis Christian (2011), Bicyclic peptide antagonists derived from genetically encoded combinatorial libraries., in Chimia
, 65(9), 677-9.
Touati Jeremy, Angelini Alessandro, Hinner Marlon J, Heinis Christian (2011), Enzymatic cyclisation of peptides with a transglutaminase., in Chembiochem : a European journal of chemical biology
, 12(1), 38-42.
Angelini Alessandro, Heinis Christian (2011), Post-translational modification of genetically encoded polypeptide libraries., in Current opinion in chemical biology
, 15(3), 355-61.
Rentero Inmaculada, Heinis Christian (2011), Screening of large molecule diversities by phage display., in Chimia
, 65(11), 843-5.
Pollaro L, Heinis C (2010), Strategies to prolong the plasma residence time of peptide drugs, in MedChemComm
, 1(5), 319-324.
Baeriswyl Vanessa, Phage selection of cyclic pepide antagonists with increased stability toward intestinal proteases, in PEDS
The excellent binding properties of antibodies and the emergence of techniques to create antibodies with any specificity have led to their use as therapeutic agents. In recent years several monoclonal antibodies have entered the clinic and have proved to be very powerful drugs for the treatment of serious medical conditions. However, due to their large molecular mass (150’000 Da) monoclonal antibodies have limitations such as the need for parenteral application by injection, poor tissue penetration, and expensive manufacturing costs.In my postdoctoral studies in the group of Sir Gregory Winter at the Laboratory of Molecular Biology (LMB) in Cambridge, UK, I proposed a strategy to generate small-molecular-weight antibody-mimicking structures by deforming peptide chains and anchoring them around small molecule building blocks. I created large combinatorial repertoires of such antibody mimics (> 4 billion different molecules) by reacting phage-displayed peptides with small molecule scaffolds. In iterative affinity selections I could isolate binders with high affinities to the human disease targets plasma kallikrein, urokinase-type plasminogen activator (uPA) and cathepsin G. The plasma kallikrein binders efficiently blocked contact activation in human plasma and may be used in cardiopulmonary bypass surgery to suppress the activation of plasma proteases upon contact of the blood with artificial surfaces (please see the manuscript Heinis, C. et al., enclosed in the application). In future, I plan to i) test the therapeutic potential of the generated binders in animal models, ii) generate antibody-mimicking structures to other protein targets iii) develop chemical scaffolds for the creation of new antibody-mimic designs, iv) test new chemical reactions to modify phage-displayed peptides, and v) spin-off the technology in a start-up company.