Identification and characterization of an atypical Gαs-biased β 2 AR agonist that fails to evoke airway smooth muscle cell tachyphylaxis | Zendy

Donghwa Kim | Zendy; А. Ю. Токмакова | Zendy; Lauren K. Lujan | Zendy; Hannah R. Strzelinski | Zendy; Nicholas Kim | Zendy; Maliheh Najari Beidokhti | Zendy; Marc A. Giulianotti | Zendy; Amirhossein Mafi | Zendy; Jung A. Woo | Zendy; Steven S. An | Zendy; William A. Goddard | Zendy; Stephen B. Liggett | Zendy

Open Access

Identification and characterization of an atypical Gαs-biased β ₂ AR agonist that fails to evoke airway smooth muscle cell tachyphylaxis

Author(s) -

Donghwa Kim,

А. Ю. Токмакова,

Lauren K. Lujan,

Hannah R. Strzelinski,

Nicholas Kim,

Maliheh Najari Beidokhti,

Marc A. Giulianotti,

Amirhossein Mafi,

Jung A. Woo,

Steven S. An,

William A. Goddard,

Stephen B. Liggett

Publication year - 2021

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.2026668118

Subject(s) - agonist , context (archaeology) , chemistry , receptor , g protein coupled receptor , desensitization (medicine) , adenylyl cyclase , biophysics , tachyphylaxis , signal transduction , arrestin , cyclic adenosine monophosphate , functional selectivity , endocrinology , medicine , microbiology and biotechnology , pharmacology , biology , biochemistry , paleontology

Significance We sought β2 AR agonists for treating obstructive lung diseases such as asthma, in which this receptor relaxes airway smooth muscle (ASM) cells and opens airways. Agonists favoring Gs coupling (leads to airway relaxation) compared with activating β-arrestin (limits effectiveness due to receptor desensitization) were pursued in a 40-million-compound screening library. Of several agonists identified, one was apparently biased away from β-arrestin. Agonist–receptor–G protein modeling revealed different receptor interactions compared with other agonists. The favorable effects of the apparent biasing with this agonist were demonstrated in a physiologic system (ASM relaxation). These studies point to a different structural class of β-agonists that might be used to treat obstructive lung diseases without the adverse effects associated with tachyphylaxis.

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