Development of anti-inflammatory peptidomimetics based on the structure of human alpha1-antitrypsin

Yotam Lior; Efrat Shtriker; Shirin Kahremany; Eli C. Lewis; Arie Gruzman

doi:10.1016/j.ejmech.2021.113969

Development of anti-inflammatory peptidomimetics based on the structure of human alpha1-antitrypsin

Yotam Lior, Efrat Shtriker, Shirin Kahremany, Eli C. Lewis, Arie Gruzman

Department of Chemistry

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

1 Scopus citations

Abstract

Human α1-antitrypsin (hAAT) has two distinguishing functions: anti-protease activity and regulation of the immune system. In the present study we hypothesized that those two protein functions are mediated by different structural domains on the hAAT surface. Indeed, such biologically active immunoregulatory sites (not associated with canonical anti-protease activity) on the surface of hAAT were identified by in silico methods. Several peptides were derived from those immunoregulatory sites. Four peptides exhibited impressive biological effects in pharmacological concentration ranges. Peptidomimetic (14) was developed, based on the structure of the most druggable and active peptide. The compound exhibited a potent anti-inflammatory activity in vitro and in vivo. Such a compound could be used as a basis for developing novel anti-inflammatory drug candidates and as a research tool for better understanding hAAT functions.

Original language	English
Article number	113969
Journal	European Journal of Medicinal Chemistry
Volume	228
DOIs	https://doi.org/10.1016/j.ejmech.2021.113969
State	Published - 15 Jan 2022

Bibliographical note

Publisher Copyright:
© 2021 Elsevier Masson SAS

Funding

This research was funded by a Bar-Ilan University new faculty grant (to A.G.) grant number 182009. S.K. was supported by the Israel Ministry of Science and Technology , Regional R&D Centers, Scholarship number 3–16752. We thank Mr. Steven Manch for the English editing. We also wish to thank Dr. Marina Vainberg and Dr. Alexander Vainberg for providing the space and scientific equipment required for this work. This research was funded by a Bar-Ilan University new faculty grant (to A.G.) grant number 182009. S.K. was supported by the Israel Ministry of Science and Technology, Regional R&D Centers, Scholarship number 3–16752. We thank Mr. Steven Manch for the English editing. We also wish to thank Dr. Marina Vainberg and Dr. Alexander Vainberg for providing the space and scientific equipment required for this work.

Funders	Funder number
Israel Ministry of Science and Technology , Regional R&D Centers	3–16752
Israel Ministry of Science and Technology, Regional R&D Centers
Bar-Ilan University	182009

Keywords

Anti-inflammatory drug candidates
Bio-active peptides
Human α1-antitrypsin
Peptidomimetics

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10.1016/j.ejmech.2021.113969

Cite this

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title = "Development of anti-inflammatory peptidomimetics based on the structure of human alpha1-antitrypsin",

abstract = "Human α1-antitrypsin (hAAT) has two distinguishing functions: anti-protease activity and regulation of the immune system. In the present study we hypothesized that those two protein functions are mediated by different structural domains on the hAAT surface. Indeed, such biologically active immunoregulatory sites (not associated with canonical anti-protease activity) on the surface of hAAT were identified by in silico methods. Several peptides were derived from those immunoregulatory sites. Four peptides exhibited impressive biological effects in pharmacological concentration ranges. Peptidomimetic (14) was developed, based on the structure of the most druggable and active peptide. The compound exhibited a potent anti-inflammatory activity in vitro and in vivo. Such a compound could be used as a basis for developing novel anti-inflammatory drug candidates and as a research tool for better understanding hAAT functions.",

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AU - Gruzman, Arie

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Development of anti-inflammatory peptidomimetics based on the structure of human alpha1-antitrypsin

Abstract

Bibliographical note

Funding

Keywords

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