Piezo-Type Mechanosensitive Ion Channel Component 1 (Piezo1): A Promising Therapeutic Target and Its Modulators

Abstract

Piezo1 is a member of the mechanosensitive piezo ion channel family, which transduces various mechanical stimulations into electrochemical signals. Piezo1 is closely implicated in different physiological processes ranging from erythrocyte volume homeostasis to lymphatic vessel formation and bone homeostasis. Aberrant Piezo1 functions caused by gain-of-function or loss-of-function mutations are associated with various pathological conditions. Due to the significant contribution on the recognition of Piezo ion channels for sensing mechanical stress, Ardem Patapoutian received the 2021 Nobel Prize in Physiology or Medicine (jointly). Strategies of targeting and modulating Piezo1 have shown potential to produce significant therapeutic effects, thus validating Piezo1 as a promising drug target for diseases. In this Perspective, we review the cryo-EM structure, mechanogating mechanism, and physiological profiles of Piezo1, together with the latest advances in the development of its modulators. Limitations and challenges as well as future development of Piezo1 modulators are discussed as well.

Binding Free Energies of Piezo1 Channel Agonists at Protein-Membrane Interface

“…Removing two chlorine atoms on ring A reduces binding affinity ( 1a ), while adding a fluorine at meta-position slightly increase the binding affinity in the open state ( 2a ). These RBFE predicted SARs are in excellent agreement with the qualitative experimental observations 26, 40 .…”

“…Removing two chlorine atoms on ring A reduces binding affinity (1a), while adding a fluorine at metaposition slightly increase the binding affinity in the open state (2a). These RBFE predicted SARs are in excellent agreement with the qualitative experimental observations 26,40 . In addition to ABFE and RBFE approaches, we seek to validate Yoda1 binding site using an orthogonal approach that does not require prior knowledge of the binding site.…”

“…We tested this idea using seven known Yoda1 analogs from literatures whose agonist activities on mouse Piezo1 are available 26, 40 . RBFE simulations were conducted using GPU accelerated AMBER-TI method with AMBER ff19SB force field (protein) and GAFF2.1 (ligand).…”

WITHDRAWN: Low-intensity pulsed ultrasound attenuates postoperative neurocognitive impairment and salvages hippocampal synaptogenesis in aged mice

“…The mechanisms of ultrasound neuromodulation have been extensively studied but not fully understood where ultrasound, as a mechanical pressure can act on mechanosensitive ion channels, has attracted much attention (31). Piezo is a mechanically sensitive ion channel that contains two isoforms, Piezo1 and Piezo2, of which Piezo1, is widely expressed in the central nervous system (32)(33)(34). Recent studies have found that ultrasound can act on Piezo1, and the activation of Piezo1 can lead to the in ux of cations like Ca 2+ , regulating downstream signaling pathways (35,36).…”

From tensegrity to human organs-on-chips: implications for mechanobiology and mechanotherapeutics

“…However, to this date, none of the drugs that target mechanosensitive channels have passed through the full clinical trial gauntlet and received FDA approval. The recent discovery of the key role that mechanosensitive Piezo channels play in various mammalian cells has raised additional excitement [ 66 ], but no new drug candidates have yet emerged. The finding that Notch, a membrane bound intercellular signaling molecule that plays a central role in differentiation and cell fate determination is also activated by mechanical forces at the cell surface [ 67 ] opens another interesting path for therapeutics development, although this has not yet been explored either.…”