TITLE: Genetic Code Reprogramming that Revolutionizes the Discovery Processes of Peptide Drug Leads
PRESENTER: Hiroaki Suga, PhD, Professor of Chemistry, Graduate School of Science, The University of Tokyo, Japan
WHEN: October 21, 6:00 PM – 7:00 PM
Meeting ID: 962 1298 0146
Genetic code reprogramming that Revolutionizes the discovery processes of peptide drug leads
Macrocyclic peptides possess a number of pharmacological characteristics distinct from other well-established therapeutic molecular classes, resulting in a versatile drug modality with a unique profile of advantages. Macrocyclic peptides are accessible by not only chemical synthesis but also ribosomal synthesis. Particularly, recent inventions of the genetic code reprogramming integrated with an in vitro display format, referred to as RaPID (Random non-standard Peptides Integrated Discovery) system, have enabled us to screen mass libraries (>1 trillion members) of non-standard peptides containing multiple non-proteinogenic amino acids, giving unique properties of peptides distinct from conventional peptides, e.g. greater proteolytic stability, higher affinity (low nM to sub nM dissociation constants similar to antibodies), and superior pharmacokinetics. The field is rapidly growing evidenced by increasing interests from industrial sectors, including small start-ups as well as mega-pharmas, toward drug development efforts on macrocyclic peptides, which has led to several de novo discovered peptides entering clinical trials. This lecture discusses the aforementioned screening technology involving the method of “genetic code reprogramming” powered by flexizymes, and several showcases of therapeutic potentials of macrocyclic peptides.
- Sakai; T. Passioura; H. Sato; K. Ito; H. Furuhashi; M. Umitsu; J. Takagi; Y. Kato; H. Mukai; S. Warashina; M. Zouda; Y. Watanabe; S. Yano; M. Shibata; H. Suga*; K. Matsumoto; “Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor” Nature chemical biology, 15, 598-606 (2019)
- Nawatha; J.M. Rogers; S.M. Bonn; I. Livneh; B. Lemma; S.M. Mali; G.B. Vamisetti; H. Sun; B. Bercovich; Y. Huang; A. Ciechanover; D. Fushman; H. Suga*; A. Brik; “De novo macrocyclic peptides that specifically modulate Lys48-linked ubiquitin chains.” Nature chemistry, 11(7):644-652 (2019)
- Kawamura, M. Münzel, T. Kojima, C. Yapp, B. Bhushan, Y. Goto, A. Tumber, T. Katoh, O.N. King, T. Passioura, L.J. Walport, S.B. Hatch, S. Madden, S. Müller, P.E. Brennan, R. Chowdhury, R.J. Hopkinson, H. Suga*, C.J. Schofield “Highly selective inhibition of histone demethylases by de novo macrocyclic peptides” Nature Communications, (2017) Apr. 6, 14773.
- Yu, P. Dranchak, Z. Li, R. MacArthur, M.S. Munson, N. Mehzabeen, N.J. Baird, K.P. Battalie, D. Ross, S. Lovell, C.K. Carlow, H. Suga*, J. Inglese,. “Macrocycle peptides delineate locked-open inhibition mechanism for microorganism phosphoglycerate mutases” Nature Communications, (2017) Apr. 3, 14932.
- Katoh; I. Wohlgemuth; M. Nagano; M.V. Rodnina; H. Suga “Essential structural elements in tRNA(Pro) for EF-P-mediated alleviation of translation stalling.” Nature communications, 7, 11657 (2016)
- Iwane; A. Hitomi; H. Murakami; T. Katoh; Y. Goto; H. Suga*, “Expanding the amino acid repertoire of ribosomal polypeptide synthesis via the artificial division of codon boxes”, Nature Chemistry, 8, 317–325 (2016)
- Ito; K. Sakai; Y. Suzuki; N. Ozawa; T. Hatta; T. Natsume; K. Matsumoto; H. Suga “Artificial human Met agonists based on macrocycle scaffolds” Nature Communications, 6, 6373 (2015)
- Terasaka, G. Hayashi, T. Katoh, H. Suga* “An orthogonal ribosome-tRNA pair via engineering of the peptidyl transferase center.” Nature Chemical Biology, 10, 555-557 (2014)
- Tanaka, C.J. Hipolito, A.D. Maturana, K. Ito, T. Kuroda, T. Higuchi. T. Katoh, H.E. Kato, M. Hattori M, K. Kumazaki, T. Tsukazaki, R. Ishitani, H. Suga, O. Nureki “Structural basis for the drug extrusion mechanism by a MATE multidrug transporter” Nature 496, 247-51 (2013).
- Goto, T. Katoh, H. Suga “Flexizymes for genetic code reprogramming” Nature Protocols 6, 779-790 (2011)
Hiroaki Suga is a Professor of the Department of Chemistry, Graduate School of Science in the University of Tokyo. He received Ph.D. at MIT (1994) followed by post-doctoral fellow in MGH (1997). He was Assistant and tenured Associate Professor in the State University of New York at Buffalo (1997-2003) and Professor in the Research Center for Advanced Science and Technology in the University of Tokyo (2003-2010). Since 2010, he has the present position. He is the recipient of Akabori Memorial Award 2014, Max-Bergmann Medal 2016, Nagoya Medal Silver 2017, Vincent du Vigneaud Award 2019, Bohlmann Lecture 2019, MIT T.Y. Shen Lecture 2020, ETHZ Prelog Lecture 2020, and The Research Award of the Alexander von Humboldt Foundation 2020 (the 2020 lectureships are postponed due to COVID-19 pandemic). He is also a founder of PeptiDream (publicly traded in the 1st section of the Tokyo Stock Exchange) and MiraBiologics in Japan.