Scientific Seminars

Hiroaki Suga is a Professor of the Department of Chemistry, Graduate School of Science in the University of Tokyo. He received his Bachelor of Engineering (1986) and Master of Engineering (1989) from Okayama University, and Ph. D. in Chemistry (1994) from the Massachusetts Institute of Technology. After three years of post-doctoral work in Massachusetts General Hospital, he became Assistant Professor in the Department of Chemistry in the State University of New York at Buffalo (1997) and promoted to the tenured Associate Professor (2002). In 2003, he moved to the Research Center for Advanced Science and Technology in the University of Tokyo. In 2010, he changed his affiliation to the Department of Chemistry, Graduate School of Science. He is the recipient of Akabori Memorial Award 2014, Japanese Peptide Society, Max-Bergmann Gold Medal 2016, Vincent du Vigneaud Award 2019, The Research Award of the Alexander von Humboldt Foundation 2020, MIT T.Y. Shen Lectureship 2022, ETHZ Prelog Medal Lecture 2022, Wolf Prize in Chemistry 2023 and others. He is also a founder of PeptiDream Inc. Tokyo, a publicly traded company in the Tokyo stock market, having many partnerships with pharmaceutical companies in worldwide. He is also a founder of MiraBiologics Inc. since 2017

Introduction
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 macrocyclic pseudo-natural 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 mega-pharmas, toward drug development efforts on macrocyclic peptides as a new modality group. This lecture discusses their screening by the RaPID system, and several showcases of therapeutic potentials of such molecules. This lecture also discusses the most recent advance in the display of pseudo-natural products generated by thiopeptide’s post-translationally modifying enzymes and the development of neobiologics using LassoGraft technology based on the macrocyclic peptide pharmacophore sequences.

References
"Designing receptor agonists with enhanced pharmacokinetics by grafting macrocyclic peptides into fragment crystallizable regions." K. Sakai; N. Sugano-Nakamura; E. Mihara; N.M. Rojas-Chaverra; S. Watanabe; H. Sato; R. Imamura; D.C. Voon; I. Sakai; C. Yamasaki; C. Tateno; M. Shibata; H. Suga; J. Takagi; K. Matsumoto, Nat. Biomed. Eng., (2022)
"Lasso-grafting of macrocyclic peptide pharmacophores yields multi-functional proteins."
E. Mihara; S. Watanabe; N.K. Bashiruddin; N. Nakamura; K. Matoba; Y. Sano; R. Maini; Y. Yin; K. Sakai; T. Arimori; K. Matsumoto; H. Suga*; J. Takagi, Nature communications, 12, 1543 (2021)
"Ribosomal Elongation of Aminobenzoic Acid Derivatives." T. Katoh; H. Suga*; Journal of the American Chemical Society, 142, 16518-16522 (2020)
"GTP-State-Selective Cyclic Peptide Ligands of K-Ras(G12D) Block Its Interaction with Raf." Z. Zhang; R. Gao; Q. Hu; H. Peacock; D.M. Peacock; S. Dai; K.M. Shokat; H. Suga* ACS Cent. Sci., (2020)
“Development of cyclic peptides with potent in vivo osteogenic activity through RaPID-based affinity maturation” N. K. Bashiruddin; M. Hayashi; M. Nagano; Y. Wu; Y. Matsunaga; J. Takagi; T. Nakashima; H. Suga*; Proceedings of the National Academy of Sciences USA 117 (49) 31070-31077 (2020)
“Ribosomal synthesis and de novo discovery of bioactive foldamer peptides containing cyclic β-amino acids” T. Katoh; T. Sengoku; K. Hirata; K. Ogata; H. Suga*; Nature Chemistry 12, 1081-1088 (2020)
"Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor"K. 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; Nature Chemical Biology, 15, 598-606 (2019)
M. 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)

Abstract:The focus of my research is to understand how the protein degradation system regulates genome stability. Over the past 15 years, we have identified chromatin-associated degradation and DNA-protein crosslink proteolysis as two protein degradation processes that are essential for genome stability, prevention of accelerated ageing and liver cancer. Surprisingly, we just discovered that autophagy, the evolutionarily conserved degradation pathway located in the cytoplasm, directly regulates DNA repair, and thus orchestrates cell survival. While it is well-established that autophagy helps maintain genome stability, evidence of its direct role in repairing DNA lesions was lacking. Through a combination of biochemical and cell biological approaches, along with quantitative proteomics, live imaging, and electron microscopy, we gained mechanistic insights into how selective autophagy directly repairs DNA damage, ultimately enabling cell survival.
My presentation will commence with an overview of protein degradation in genome stability and subsequently delve into the specific role of selective autophagy in DNA repair and maintaining genome stability.

Zoom link - https://mrc-lmb-cam-ac-uk.zoom.us/j/98964505344?pwd=T3VtMDE2aUpXTGRLNCtwU3RnNEdHdz09

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Zoom link - https://mrc-lmb-cam-ac-uk.zoom.us/j/91614790739?pwd=QncrTFFvNG1xWVZJOWhqL0lTcHVIQT09

Zoom link - https://mrc-lmb-cam-ac-uk.zoom.us/j/94960208716?pwd=bVF4L1JVYnlnNkhIcXFmYld6TXo5QT09

Zoom link - https://mrc-lmb-cam-ac-uk.zoom.us/j/96608781341?pwd=MG5QMXVmOStXcFVtalBqUlBYc0tEdz09

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