Rapid Discovery of Potent and Selective Glycosidase-Inhibiting De Novo Peptides

S.A.K. Jongkees; S. Caner; C. Tysoe; G.D. Brayer; S.G. Withers; H. Suga

doi:10.1016/j.chembiol.2017.02.001

Rapid Discovery of Potent and Selective Glycosidase-Inhibiting De Novo Peptides

S.A.K. Jongkees, S. Caner, C. Tysoe, G.D. Brayer, S.G. Withers, H. Suga

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

© 2017 Elsevier LtdHuman pancreatic α-amylase (HPA) is responsible for degrading starch to malto-oligosaccharides, thence to glucose, and is therefore an attractive therapeutic target for the treatment of diabetes and obesity. Here we report the discovery of a unique lariat nonapeptide, by means of the RaPID (Random non-standard Peptides Integrated Discovery) system, composed of five amino acids in a head-to-side-chain thioether macrocycle and a further four amino acids in a 310helical C terminus. This is a potent inhibitor of HPA (Ki = 7 nM) yet exhibits selectivity for the target over other glycosidases tested. Structural studies show that this nonapeptide forms a compact tertiary structure, and illustrate that a general inhibitory motif involving two phenolic groups is often accessed for tight binding of inhibitors to HPA. Furthermore, the work reported here demonstrates the potential of this methodology for the discovery of de novo peptide inhibitors against other glycosidases.

Original language	English
Pages (from-to)	381-390
Journal	Cell Chemical Biology
Volume	24
Issue number	3
DOIs	https://doi.org/10.1016/j.chembiol.2017.02.001
Publication status	Published - 16 Mar 2017
Externally published	Yes

Funding

This work was supported by the Japan Agency for Medical Research and Development, Basic Science and Platform Technology Program for Innovative Biological Medicine (to H.S.), operating grants from the Canadian Glycomics Network/Networks of Centres of Excellence (Project DO-2; to G.D.B. and S.G.W.), and a Japan Society for the Promotion of Science post-doctoral fellowship (P13026, to S.A.K.J.). S.G.W. is supported by a Tier 1 Canada Research Chair. We would like to thank Emily Kwan for supplying the wild-type HPA used in the selection and Nham T. Nguyen for technical assistance; Dr. David R. Rose for supplying mammalian intestinal α-glucosidases; Dr. Frank Huvers for critical reading on diabetes relevance; and Dr. Nikita Loik for co-writing the Python script for high-throughput sequence data processing. Portions of this research were carried out at the Stanford Synchrotron Radiation Lightsource, SLAC National Accelerator Laboratory, which is supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. DE-AC02-76SF00515. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the NIH, National Institute of General Medical Sciences (including P41GM103393). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.

Funders	Funder number
Canadian Glycomics Network/Networks of Centres of Excellence	DO-2
Tier 1 Canada Research Chair
National Institutes of Health
U.S. Department of Energy
National Institute of General Medical Sciences	P41GM103393
Office of Science
Basic Energy Sciences	DE-AC02-76SF00515
Biological and Environmental Research
Japan Agency for Medical Research and Development
Japan Society for the Promotion of Science	P13026

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title = "Rapid Discovery of Potent and Selective Glycosidase-Inhibiting De Novo Peptides",

abstract = "{\textcopyright} 2017 Elsevier LtdHuman pancreatic α-amylase (HPA) is responsible for degrading starch to malto-oligosaccharides, thence to glucose, and is therefore an attractive therapeutic target for the treatment of diabetes and obesity. Here we report the discovery of a unique lariat nonapeptide, by means of the RaPID (Random non-standard Peptides Integrated Discovery) system, composed of five amino acids in a head-to-side-chain thioether macrocycle and a further four amino acids in a 310helical C terminus. This is a potent inhibitor of HPA (Ki = 7 nM) yet exhibits selectivity for the target over other glycosidases tested. Structural studies show that this nonapeptide forms a compact tertiary structure, and illustrate that a general inhibitory motif involving two phenolic groups is often accessed for tight binding of inhibitors to HPA. Furthermore, the work reported here demonstrates the potential of this methodology for the discovery of de novo peptide inhibitors against other glycosidases.",

author = "S.A.K. Jongkees and S. Caner and C. Tysoe and G.D. Brayer and S.G. Withers and H. Suga",

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AU - Jongkees, S.A.K.

AU - Caner, S.

AU - Tysoe, C.

AU - Brayer, G.D.

AU - Withers, S.G.

AU - Suga, H.

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N2 - © 2017 Elsevier LtdHuman pancreatic α-amylase (HPA) is responsible for degrading starch to malto-oligosaccharides, thence to glucose, and is therefore an attractive therapeutic target for the treatment of diabetes and obesity. Here we report the discovery of a unique lariat nonapeptide, by means of the RaPID (Random non-standard Peptides Integrated Discovery) system, composed of five amino acids in a head-to-side-chain thioether macrocycle and a further four amino acids in a 310helical C terminus. This is a potent inhibitor of HPA (Ki = 7 nM) yet exhibits selectivity for the target over other glycosidases tested. Structural studies show that this nonapeptide forms a compact tertiary structure, and illustrate that a general inhibitory motif involving two phenolic groups is often accessed for tight binding of inhibitors to HPA. Furthermore, the work reported here demonstrates the potential of this methodology for the discovery of de novo peptide inhibitors against other glycosidases.

AB - © 2017 Elsevier LtdHuman pancreatic α-amylase (HPA) is responsible for degrading starch to malto-oligosaccharides, thence to glucose, and is therefore an attractive therapeutic target for the treatment of diabetes and obesity. Here we report the discovery of a unique lariat nonapeptide, by means of the RaPID (Random non-standard Peptides Integrated Discovery) system, composed of five amino acids in a head-to-side-chain thioether macrocycle and a further four amino acids in a 310helical C terminus. This is a potent inhibitor of HPA (Ki = 7 nM) yet exhibits selectivity for the target over other glycosidases tested. Structural studies show that this nonapeptide forms a compact tertiary structure, and illustrate that a general inhibitory motif involving two phenolic groups is often accessed for tight binding of inhibitors to HPA. Furthermore, the work reported here demonstrates the potential of this methodology for the discovery of de novo peptide inhibitors against other glycosidases.

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Rapid Discovery of Potent and Selective Glycosidase-Inhibiting De Novo Peptides

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