Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3

Michael Weinmüller; Florian Rechenmacher; Udaya Kiran Marelli; Florian Reichart; Tobias G. Kapp; Andreas F.B. Räder; Francesco Saverio Di Leva; Luciana Marinelli; Ettore Novellino; José M. Muñoz-Félix; Kairbaan Hodivala-Dilke; Adi Schumacher; Joseph Fanous; Chaim Gilon; Amnon Hoffman; Horst Kessler

doi:10.1002/anie.201709709

Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3

Michael Weinmüller, Florian Rechenmacher, Udaya Kiran Marelli, Florian Reichart, Tobias G. Kapp, Andreas F.B. Räder, Francesco Saverio Di Leva, Luciana Marinelli, Ettore Novellino, José M. Muñoz-Félix, Kairbaan Hodivala-Dilke, Adi Schumacher, Joseph Fanous, Chaim Gilon, Amnon Hoffman, Horst Kessler^*

^*Corresponding author for this work

School of Pharmacy

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

A highly systematic approach for the development of both orally bioavailable and bioactive cyclic N-methylated hexapeptides as high affinity ligands for the integrin αvβ3 is based on two concepts: a) screening of systematically designed libraries with spatial diversity and b) masking of the peptide charge with a lipophilic protecting group. The key steps of the method are 1) initial design of a combinatorial library of N-methylated analogues of the stem peptide cyclo(d-Ala-Ala₅); 2) selection of cyclic peptides with the highest intestinal permeability; 3) design of sublibraries with the bioactive RGD sequence in all possible positions; 4) selection of the best ligands for RGD-recognizing integrin subtypes; 5) fine-tuning of the affinity and selectivity by additional Ala to Xaa substitutions; 6) protection of the charged functional groups according to the prodrug concept to regain intestinal and oral permeability; 7) proof of biological effects in mice after oral administration.

Original language	American English
Pages (from-to)	16405-16409
Number of pages	5
Journal	Angewandte Chemie - International Edition
Volume	56
Issue number	51
DOIs	https://doi.org/10.1002/anie.201709709
State	Published - 18 Dec 2017

Bibliographical note

Funding Information:
This work was supported by the Reinhart Koselleck Grant of the Deutsche Forschungsgemeinschaft (DFG KE 147/42-1) and by CIPSM to H.K. The ex vivo and in vivo studies were supported by Worldwide Cancer Research (16-0390) and Cancer Research UK C8218/A18673, PI KHD. We also acknowledge MIUR-PRIN 2015 (Grant ID: FCHJ8E; L.M.).

Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Keywords

cyclic peptides
drug design
integrin ligands
oral bioavailability
prodrugs

Access to Document

10.1002/anie.201709709

Cite this

Weinmüller, M., Rechenmacher, F., Kiran Marelli, U., Reichart, F., Kapp, T. G., Räder, A. F. B., Di Leva, F. S., Marinelli, L., Novellino, E., Muñoz-Félix, J. M., Hodivala-Dilke, K., Schumacher, A., Fanous, J., Gilon, C., Hoffman, A., & Kessler, H. (2017). Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3. Angewandte Chemie - International Edition, 56(51), 16405-16409. https://doi.org/10.1002/anie.201709709

@article{dbe6f45f202b4a13a1aedba7ce84aaa1,

title = "Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3",

abstract = "A highly systematic approach for the development of both orally bioavailable and bioactive cyclic N-methylated hexapeptides as high affinity ligands for the integrin αvβ3 is based on two concepts: a) screening of systematically designed libraries with spatial diversity and b) masking of the peptide charge with a lipophilic protecting group. The key steps of the method are 1) initial design of a combinatorial library of N-methylated analogues of the stem peptide cyclo(d-Ala-Ala5); 2) selection of cyclic peptides with the highest intestinal permeability; 3) design of sublibraries with the bioactive RGD sequence in all possible positions; 4) selection of the best ligands for RGD-recognizing integrin subtypes; 5) fine-tuning of the affinity and selectivity by additional Ala to Xaa substitutions; 6) protection of the charged functional groups according to the prodrug concept to regain intestinal and oral permeability; 7) proof of biological effects in mice after oral administration.",

keywords = "cyclic peptides, drug design, integrin ligands, oral bioavailability, prodrugs",

author = "Michael Weinm{\"u}ller and Florian Rechenmacher and {Kiran Marelli}, Udaya and Florian Reichart and Kapp, {Tobias G.} and R{\"a}der, {Andreas F.B.} and {Di Leva}, {Francesco Saverio} and Luciana Marinelli and Ettore Novellino and Mu{\~n}oz-F{\'e}lix, {Jos{\'e} M.} and Kairbaan Hodivala-Dilke and Adi Schumacher and Joseph Fanous and Chaim Gilon and Amnon Hoffman and Horst Kessler",

note = "Funding Information: This work was supported by the Reinhart Koselleck Grant of the Deutsche Forschungsgemeinschaft (DFG KE 147/42-1) and by CIPSM to H.K. The ex vivo and in vivo studies were supported by Worldwide Cancer Research (16-0390) and Cancer Research UK C8218/A18673, PI KHD. We also acknowledge MIUR-PRIN 2015 (Grant ID: FCHJ8E; L.M.). Publisher Copyright: {\textcopyright} 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.",

year = "2017",

month = dec,

day = "18",

doi = "10.1002/anie.201709709",

language = "American English",

volume = "56",

pages = "16405--16409",

journal = "Angewandte Chemie - International Edition",

issn = "1433-7851",

publisher = "John Wiley and Sons Ltd",

number = "51",

}

Weinmüller, M, Rechenmacher, F, Kiran Marelli, U, Reichart, F, Kapp, TG, Räder, AFB, Di Leva, FS, Marinelli, L, Novellino, E, Muñoz-Félix, JM, Hodivala-Dilke, K, Schumacher, A, Fanous, J, Gilon, C, Hoffman, A & Kessler, H 2017, 'Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3', Angewandte Chemie - International Edition, vol. 56, no. 51, pp. 16405-16409. https://doi.org/10.1002/anie.201709709

Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3. / Weinmüller, Michael; Rechenmacher, Florian; Kiran Marelli, Udaya et al.
In: Angewandte Chemie - International Edition, Vol. 56, No. 51, 18.12.2017, p. 16405-16409.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Overcoming the Lack of Oral Availability of Cyclic Hexapeptides

T2 - Design of a Selective and Orally Available Ligand for the Integrin αvβ3

AU - Weinmüller, Michael

AU - Rechenmacher, Florian

AU - Kiran Marelli, Udaya

AU - Reichart, Florian

AU - Kapp, Tobias G.

AU - Räder, Andreas F.B.

AU - Di Leva, Francesco Saverio

AU - Marinelli, Luciana

AU - Novellino, Ettore

AU - Muñoz-Félix, José M.

AU - Hodivala-Dilke, Kairbaan

AU - Schumacher, Adi

AU - Fanous, Joseph

AU - Gilon, Chaim

AU - Hoffman, Amnon

AU - Kessler, Horst

N1 - Funding Information: This work was supported by the Reinhart Koselleck Grant of the Deutsche Forschungsgemeinschaft (DFG KE 147/42-1) and by CIPSM to H.K. The ex vivo and in vivo studies were supported by Worldwide Cancer Research (16-0390) and Cancer Research UK C8218/A18673, PI KHD. We also acknowledge MIUR-PRIN 2015 (Grant ID: FCHJ8E; L.M.). Publisher Copyright: © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

PY - 2017/12/18

Y1 - 2017/12/18

N2 - A highly systematic approach for the development of both orally bioavailable and bioactive cyclic N-methylated hexapeptides as high affinity ligands for the integrin αvβ3 is based on two concepts: a) screening of systematically designed libraries with spatial diversity and b) masking of the peptide charge with a lipophilic protecting group. The key steps of the method are 1) initial design of a combinatorial library of N-methylated analogues of the stem peptide cyclo(d-Ala-Ala5); 2) selection of cyclic peptides with the highest intestinal permeability; 3) design of sublibraries with the bioactive RGD sequence in all possible positions; 4) selection of the best ligands for RGD-recognizing integrin subtypes; 5) fine-tuning of the affinity and selectivity by additional Ala to Xaa substitutions; 6) protection of the charged functional groups according to the prodrug concept to regain intestinal and oral permeability; 7) proof of biological effects in mice after oral administration.

AB - A highly systematic approach for the development of both orally bioavailable and bioactive cyclic N-methylated hexapeptides as high affinity ligands for the integrin αvβ3 is based on two concepts: a) screening of systematically designed libraries with spatial diversity and b) masking of the peptide charge with a lipophilic protecting group. The key steps of the method are 1) initial design of a combinatorial library of N-methylated analogues of the stem peptide cyclo(d-Ala-Ala5); 2) selection of cyclic peptides with the highest intestinal permeability; 3) design of sublibraries with the bioactive RGD sequence in all possible positions; 4) selection of the best ligands for RGD-recognizing integrin subtypes; 5) fine-tuning of the affinity and selectivity by additional Ala to Xaa substitutions; 6) protection of the charged functional groups according to the prodrug concept to regain intestinal and oral permeability; 7) proof of biological effects in mice after oral administration.

KW - cyclic peptides

KW - drug design

KW - integrin ligands

KW - oral bioavailability

KW - prodrugs

UR - http://www.scopus.com/inward/record.url?scp=85034834765&partnerID=8YFLogxK

U2 - 10.1002/anie.201709709

DO - 10.1002/anie.201709709

M3 - Article

C2 - 29072809

AN - SCOPUS:85034834765

SN - 1433-7851

VL - 56

SP - 16405

EP - 16409

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 51

ER -

Overcoming the Lack of Oral Availability of Cyclic Hexapeptides: Design of a Selective and Orally Available Ligand for the Integrin αvβ3

Abstract

Bibliographical note

Keywords

Access to Document

Other files and links

Fingerprint

Cite this