DNA-encoded chemical libraries; Tumor targeting; Pharmacodelivery; Drug release; Macrocycles; Smart drugs
Stress Cedric, Sauter Basilius, Schneider Lukas, Sharpe Timothy, Gillingham Dennis (2019), A DNA-encoded chemical library incorporating elements of natural macrocycles, in Angewandte Chemie International Edition
Cazzamalli Samuele, Ziffels Barbara, Widmayer Fontaine, Murer Patrizia, Pellegrini Giovanni, Pretto Francesca, Wulhfard Sarah, Neri Dario (2018), Enhanced Therapeutic Activity of Non-Internalizing Small-Molecule-Drug Conjugates Targeting Carbonic Anhydrase IX in Combination with Targeted Interleukin-2, in Clinical Cancer Research
, 24(15), 3656-3667.
Favalli Nicholas, Biendl Stefan, Hartmann Marco, Piazzi Jacopo, Sladojevich Filippo, Gräslund Susanne, Brown Peter J., Näreoja Katja, Schüler Herwig, Scheuermann Jörg, Franzini Raphael, Neri Dario (2018), A DNA-Encoded Library of Chemical Compounds Based on Common Scaffolding Structures Reveals the Impact of Ligand Geometry on Protein Recognition, in ChemMedChem
, 13(13), 1303-1307.
Grisoni Francesca, Neuhaus Claudia S., Gabernet Gisela, Müller Alex T., Hiss Jan A., Schneider Gisbert (2018), Designing Anticancer Peptides by Constructive Machine Learning, in ChemMedChem
, 13(13), 1300-1302.
Neri Dario, Lerner Richard A. (2018), DNA-Encoded Chemical Libraries: A Selection System Based on Endowing Organic Compounds with Amplifiable Information, in Annual Review of Biochemistry
, 87(1), 479-502.
Favalli Nicholas, Bassi Gabriele, Scheuermann Jörg, Neri Dario (2018), DNA-encoded chemical libraries - achievements and remaining challenges, in FEBS Letters
, 592(12), 2168-2180.
Li Yizhou, De Luca Roberto, Cazzamalli Samuele, Pretto Francesca, Bajic Davor, Scheuermann Jörg, Neri Dario (2018), Versatile protein recognition by the encoded display of multiple chemical elements on a constant macrocyclic scaffold, in Nature Chemistry
, 10(4), 441-448.
Cazzamalli Samuele, Dal Corso Alberto, Widmayer Fontaine, Neri Dario (2018), Chemically Defined Antibody– and Small Molecule–Drug Conjugates for in Vivo Tumor Targeting Applications: A Comparative Analysis, in Journal of the American Chemical Society
, 140(5), 1617-1621.
Pillong Max, Hiss Jan A., Schneider Petra, Lin Yen-Chu, Posselt Gernot, Pfeiffer Bernhard, Blatter Markus, Müller Alex T., Bachler Simon, Neuhaus Claudia S., Dittrich Petra S., Altmann Karl-Heinz, Wessler Silja, Schneider Gisbert (2017), Rational Design of Membrane-Pore-Forming Peptides, in Small
, 13(40), 1701316-1701316.
Dal Corso Alberto, Gébleux Rémy, Murer Patrizia, Soltermann Alex, Neri Dario (2017), A non-internalizing antibody-drug conjugate based on an anthracycline payload displays potent therapeutic activity in vivo, in Journal of Controlled Release
, 264, 211-218.
Dal Corso Alberto, Cazzamalli Samuele, Gébleux Rémy, Mattarella Martin, Neri Dario (2017), Protease-Cleavable Linkers Modulate the Anticancer Activity of Noninternalizing Antibody–Drug Conjugates, in Bioconjugate Chemistry
Zimmermann Gunther, Rieder Ulrike, Bajic Davor, Vanetti Sara, Chaikuad Apirat, Knapp Stefan, Scheuermann Jorg, Mattarella Martin, Neri Dario (2017), A Specific and Covalent JNK-1 Ligand Selected from an Encoded Self-Assembling Chemical Library, in CHEMISTRY-A EUROPEAN JOURNAL
, (34), 8152-8155.
Müller Alex T., Gabernet Gisela, Hiss Jan A., Schneider Gisbert (2017), modlAMP: Python for antimicrobial peptides, in Bioinformatics
Zimmermann Gunther, Li Yizhou, Rieder Ulrike, Mattarella Martin, Neri Dario, Scheuermann Jorg (2017), Hit-Validation Methodologies for Ligands Isolated from DNA-Encoded Chemical Libraries, in CHEMBIOCHEM
, (9), 853-857.
Li Yizhou, Zimmermann Gunther, Scheuermann Joerg, Neri Dario (2017), Quantitative PCR is a Valuable Tool to Monitor the Performance of DNA-Encoded Chemical Library Selections, in CHEMBIOCHEM
, (9), 848-852.
Gébleux Rémy, Stringhini Marco, Casanova Ruben, Soltermann Alex, Neri Dario (2017), Non-internalizing antibody-drug conjugates display potent anti-cancer activity upon proteolytic release of monomethyl auristatin E in the subendothelial extracellular matrixNon-internalizing antibody-drug conjugates and their anti-cancer activity, in International Journal of Cancer
, 140(7), 1670-1679.
Schneider Petra, Müller Alex T., Gabernet Gisela, Button Alexander L., Posselt Gernot, Wessler Silja, Hiss Jan A., Schneider Gisbert (2017), Hybrid Network Model for “Deep Learning” of Chemical Data: Application to Antimicrobial Peptides, in Molecular Informatics
, 36(1-2), 1600011-1600011.
Armbrecht Lucas, Gabernet Gisela, Kurth Felix, Hiss Jan A, Schneider Gisbert, Dittrich Petra S (2017), Characterisation of anticancer peptides at the single-cell level, in Lab Chip
Cazzamalli Samuele, Corso Alberto Dal, Neri Dario (2017), Linker stability influences the anti-tumor activity of acetazolamide-drug conjugates for the therapy of renal cell carcinoma, in Journal of Controlled Release
Decurtins Willy, Wichert Moreno, Franzini Raphael M, Buller Fabian, Stravs Michael A, Zhang Yixin, Neri Dario, Scheuermann Jörg (2016), Automated screening for small organic ligands using DNA-encoded chemical libraries, in Nature Protocols
, 11(4), 764-780.
Cazzamalli S., Dal Corso A., Neri D. (2016), Acetazolamide Serves as Selective Delivery Vehicle for Dipeptide-Linked Drugs to Renal Cell Carcinoma, in Molecular Cancer Therapeutics
, (12), 2926-2935.
Li Yizhou, Gabriele Elena, Samain Florent, Favalli Nicholas, Sladojevich Filippo, Scheuermann Jörg, Neri Dario (2016), Optimized Reaction Conditions for Amide Bond Formation in DNA-Encoded Combinatorial Libraries., in ACS combinatorial science
Gébleux Rémy, Wulhfard Sarah, Casi Giulio, Neri Dario (2015), Antibody Format and Drug Release Rate Determine the Therapeutic Activity of Noninternalizing Antibody-Drug Conjugates., in Molecular cancer therapeutics
, (11), 2606-12.
We will build a general and broadly-applicable platform technology for the targeted delivery of drugs. In contrast to current approaches our targeting motifs will derive from libraries of modular small molecule macrocyclic scaffolds, opening the door to a variety of previously inaccessible targets. Our guided drugs will be designed to be released at the target through the development of smart linkers that respond to a disease microenvironment or cell receptor. The drugs themselves will derive from known compounds complemented by designs created in the Schneider group. Many pharmaceutical agents are unselective, causing toxicity to normal organs and preventing dose escalation to therapeutically active regimens. Selectively delivering and activating drugs at the site of disease holds great promise for dramatically increasing the therapeutic index of bioactive molecules, thus providing substantial benefits to patients. A successful general platform that exploits small ligands for pharmacodelivery applications would represent a transformative innovation for both academia and industry.Current strategies for targeted drug delivery rely mainly on antibodies as “vehicles”, but recent disappointments in Phase III clinical trials (>5 high-profile clinical failures) with antibody-drug conjugates call into question their real value. Moreover, because of their large size and unacceptably high cost, antibodies can only be used for delivering ultra-potent drugs, hindering development opportunities with conventional pharmaceutical agents and in areas outside oncology. A handful of naturally-occurring small organic ligands for common receptors (folate receptor, carbonic anhydrase IX) have been proposed as an alternative to antibodies for pharmacodelivery strategies, but a general approach that avoids large biomolecules has not been described due to limitations in ligand discovery and to the lack of suitable strategies for drug release at the site of disease. The ability to create “smart drugs” will emerge from advances made in each of the subgroups: Specifically, we will construct encoded chemical libraries of unprecedented size and quality (dozens of millions of compounds) and screen these libraries for ligands against at least ten validated accessible markers of cancer and chronic inflammation. In addition, we will develop and implement innovative technologies for the smart release and activation of bioactive payloads at the site of disease. The linker/release triggers for therapeutic payloads will be tailored to respond to the disease microenvironment and to selectively act on the target cells of choice. In addition to employing well-known cytotoxic agents like tubulin inhibitors (DM1, MMAE) as payloads, we will primarily explore the use of membrane-disruptive peptides. These designed cytotoxic peptides have the unique advantage of (i) directly addressing the plasma membrane of cancer cells as target without the involvement of proteins, which minimizes the risk of cancer cell escape by mutation or development of resistances; (ii) cancer cell-selective membrane targeting as a result of our molecular design aiming at custom-tailored highly potent cytotoxic peptide payloads; and (iii) rapid plasma clearance so that the peptides, once released from the carrier, will act only locally at the site of release, thereby minimizing unwanted off-target and side-effects.The proposal is bold, requiring expertise in chemical, biochemical, and computational technology - a combination beyond the reach of any one research group. The synergy created through the participation of three complementary teams is essential. Prof. Neri (ETH Zürich) will be responsible for the production of target proteins, for the construction and screening of DNA-encoded libraries of chemically-modified cyclic peptides, for the development of small molecule-drug conjugates and for in vivo testing of the most promising compounds in mouse models of cancer and of rheumatoid arthritis. Prof. Gillingham (University of Basel) will be responsible for creating macrocycle libraries, importing them into the DNA encoded format, as well as developing new redox-responsive cleavable linkers. Prof. Schneider (ETH Zürich) will be responsible for the computational design, chemical synthesis, biochemical testing and engineering of novel peptide cytotoxins that kill target cells from the outside by direct cancer cell disruption.