Dual antagonists of α5β1/αvβ1 integrin for airway hyperresponsiveness - PubMed (original) (raw)

. 2020 Nov 15;30(22):127578.

doi: 10.1016/j.bmcl.2020.127578. Epub 2020 Sep 29.

Chun Chen 2, Nilgun Isik Reed 1, Sean Liu 3, Seul Ki Yeon 4, Joel McIntosh 4, You-Zhi Tang 4, Hyunjun Yang 4, Marc Adler 5, Richard Beresis 5, Ian B Seiple 4, Dean Sheppard 1, William F DeGrado 4, Hyunil Jo 6

Affiliations

Dual antagonists of α5β1/αvβ1 integrin for airway hyperresponsiveness

Aparna Sundaram et al. Bioorg Med Chem Lett. 2020.

Abstract

Inhibition of integrin α5β1 emerges as a novel therapeutic option to block transmission of contractile forces during asthma attack. We designed and synthesized novel inhibitors of integrin α5β1 by backbone replacement of known αvβ1 integrin inhibitors. These integrin α5β1 inhibitors also retain the nanomolar potency against αvβ1 integrin, which shows promise for developing dual integrin α5β1/αvβ1 inhibitor. Introduction of hydrophobic adamantane group significantly boosted the potency as well as selectivity over integrin αvβ3. We also demonstrated one of the inhibitors (11) reduced airway hyperresponsiveness in ex vivo mouse tracheal ring assay. Results from this study will help guide further development of integrin α5β1 inhibitors as potential novel asthma therapeutics.

Keywords: Asthma; Integrin inhibitor; Integrin α5β1; Integrin αvβ1; RGD integrin.

Copyright © 2020 Elsevier Ltd. All rights reserved.

PubMed Disclaimer

Conflict of interest statement

Declaration of Competing Interest

W.F.D. and D. S. have an equity interest in Pliant Therapeutics which conducts work in a similar area of research. W.F.D. and D.S. are founders and scientific advisory board members and C.C. is an employee of Pliant Therapeutics.

Declaration of interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1.

Figure 1.

Structures of α5β1 integrin inhibitors 1–3 and αvβ1 integrin inhibitors 4–5

Figure 2.

Figure 2.. A model of 17 (orange) bound to α5β1.

The model is based on the published α5β1 structure 4wk0.pdb and has been minimized using MOE/CCG. A) Connelly surface of the model. The green patch shows selected hydrophobic side chains of α5: Phe155, Trp157, Ala159, & Phe187. B) Same α5β1 model (green) shown as above w/o surface. The cyan atoms represent the crystal structure of αvβ3, 3ije.pdb. Four hydrophilic substitutions are highlighted in the αv chain that attenuate the affinity for the adamantine group in 17.

Figure 3.

Figure 3.. Mouse trachea ring contraction assay

Force exerted on WT mouse tracheal rings measured after incubation for 12 h with IL-13 (100 ng/mL), then 1 h with compound 11 or vehicle with a range of concentrations of methacholine. Negative controls without IL-13 treatment are also shown. n=3 rings per group. **P<0.01, repeated measures of variance.

Scheme 1

Scheme 1

Synthesis of 8-15 Reagents and Conditions: a) N-benzenesulfonyl-L-proline, HCTU, DIPEA, b) 4M HCl in dioxane (70% for the two steps) c) RNHCO2PhNO2, DIPEA or R’CO2H, HCTU, DIPEA, d) Boc-Gly, HCTU, DIPEA e) 4M HCl in dioxane f) R’’CO2H, HCTU, DIPEA g) TFA, DCM h) LiOH, THF-H2O. See the Supplementary data for details of syntheses.

References

    1. Postma DS; Kerstjens HA, Characteristics of airway hyperresponsiveness in asthma and chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1998, 158 (5 Pt 3), S187–92. -PubMed
    1. Bateman ED; Hurd SS; Barnes PJ; Bousquet J; Drazen JM; FitzGerald JM; Gibson P; Ohta K; O’Byrne P; Pedersen SE; Pizzichini E; Sullivan SD; Wenzel SE; Zar HJ, Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008, 31 (1), 143–78. -PubMed
    1. Antonicelli L; Bucca C; Neri M; De Benedetto F; Sabbatani P; Bonifazi F; Eichler HG; Zhang Q; Yin DD, Asthma severity and medical resource utilisation. Eur Respir J 2004, 23 (5), 723–9. -PubMed
    1. Barnes PJ, Targeting cytokines to treat asthma and chronic obstructive pulmonary disease. Nat Rev Immunol 2018, 18 (7), 454–466. -PubMed
    1. Eger KA; Bel EH, The emergence of new biologics for severe asthma. Curr Opin Pharmacol 2019, 46, 108–115. -PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources