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Last update 23 Jan 2025

Calpain1/2

Last update 23 Jan 2025

Basic Info

Synonyms

C2: Calpain

Introduction-

Drugs associated with Calpain1/2

CEP-4143

Target

Calpain1/2

Mechanism

Calpain1/2 inhibitors

Active Org.-

Originator Org.

Cephalon, Inc.

Active Indication-

Inactive Indication

Neurodegenerative Diseases [+1]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

C-101

Target

Calpain1/2

Mechanism

Calpain1/2 inhibitors

Active Org.-

Originator Org.

Ceptor Corp. (Maryland)

Active Indication-

Inactive Indication

Muscular Dystrophies

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Restenex

Target

Calpain1/2

Mechanism

Calpain1/2 inhibitors

Active Org.-

Originator Org.

Cortex Pharmaceuticals, Inc. /Private Group/

Active Indication-

Inactive Indication

Vascular restenosis

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with Calpain1/2

NCT04001998

/ WithdrawnPhase 1

A Two-Part, Open Label, Complete Crossover Study to Compare the Tablet and Capsule Formulations of BLD-2660, Including a Food Effect Assessment of the Tablet Formulation, and to Assess Dose Proportionality Following Single Oral Doses of BLD-2660 in Tablet Formulation

Single center, randomized, open label, two-part crossover study designed to evaluate the PK, food effect, dose proportionality, safety, and tolerability of BLD-2660 in healthy volunteers.

Start Date01 Feb 2021

Sponsor / Collaborator

Blade Therapeutics, Inc.

EUCTR2019-004998-34-GB

/ Not yet recruitingPhase 2

A Phase 2a, Double-Blind, Placebo-Controlled Study to Evaluate Pharmacodynamics, Pharmacokinetics, and Safety of BLD-2660 Administered Orally in Subjects with Idiopathic Pulmonary Fibrosis - B-2660-203

Start Date16 Jul 2020

Sponsor / Collaborator

Blade Therapeutics, Inc.

RBR-2kjm6y

/ RecruitingPhase 2

A phase 2 randomized double-blind placebo-controlled study to evaluate safety and antiviral activity of BLD-2660 in hospitalized subjects with recently diagnosed COVID-19 compared to standard of care treatment

Start Date22 May 2020

Sponsor / Collaborator

Blade Therapeutics, Inc.

100 Clinical Results associated with Calpain1/2

100 Translational Medicine associated with Calpain1/2

0 Patents (Medical) associated with Calpain1/2

Literatures (Medical) associated with Calpain1/2

31 Oct 2023·The Journal of Biochemistry

Calpain-3 not only proteolyzes calpain-1 and -2 but also is a substrate for calpain-1 and -2

Article

Author: Ojima, Koichi ; Hata, Shoji ; Ono, Yasuko ; Muroya, Susumu ; Shinkai-Ouchi, Fumiko

AbstractCalpain is an intracellular cysteine protease that cleaves its specific substrates in a limited region to modulate cellular function. Calpain-1 (C1) and calpain-2 (C2) are ubiquitously expressed in mammalian cells, but calpain-3 (C3) is a skeletal muscle-specific type. In the course of calpain activation, the N-terminal regions of all three isoforms are clipped off in an intramolecular or intermolecular fashion. C1 proteolyzes C2 to promote further proteolysis, but C2 proteolyzes C1 to suspend C1 proteolysis, indicating the presence of C1–C2 reciprocal proteolysis. However, whether C3 is involved in the calpain proteolysis network is unclear. To address this, we examined whether GFP-tagged C3:C129S (GFP-C3:CS), an inactive protease form of C3, was a substrate for C1 or C2 in HEK cells. Intriguingly, the N-terminal region of C3:CS was cleaved by C1 and C2 at the site identical to that of the C3 autoproteolysis site. Furthermore, the N-terminal clipping of C3:CS by C1 and C2 was observed in mouse skeletal muscle lysates. Meanwhile, C3 preferentially cleaved the N-terminus of C1 over that of C2, and the sizes of these cleaved proteins were identical to their autoproteolysis forms. Our findings suggest an elaborate inter-calpain network to prime and suppress proteolysis of other calpains.

29 Apr 2022·Science Advances

Lactate induces vascular permeability via disruption of VE-cadherin in endothelial cells during sepsis

Article

Author: Fan, Min ; Gill, P. Spencer ; Wang, Yana ; Li, Chuanfu ; Liu, Li ; Hall, Jennifer V. ; Xu, Jingjing ; Wang, Xiaohui ; Williams, David L. ; Yang, Kun ; Ha, Tuanzhu

Circulating lactate levels are a critical biomarker for sepsis and are positively correlated with sepsis-associated mortality. We investigated whether lactate plays a biological role in causing endothelial barrier dysfunction in sepsis. We showed that lactate causes vascular permeability and worsens organ dysfunction in CLP sepsis. Mechanistically, lactate induces ERK-dependent activation of calpain1/2 for VE-cadherin proteolytic cleavage, leading to the enhanced endocytosis of VE-cadherin in endothelial cells. In addition, we found that ERK2 interacts with VE-cadherin and stabilizes VE-cadherin complex in resting endothelial cells. Lactate-induced ERK2 phosphorylation promotes ERK2 disassociation from VE-cadherin. In vivo suppression of lactate production or genetic depletion of lactate receptor GPR81 mitigates vascular permeability and multiple organ injury and improves survival outcome in polymicrobial sepsis. Our study reveals that metabolic cross-talk between glycolysis-derived lactate and the endothelium plays a critical role in the pathophysiology of sepsis.

30 Apr 2021·Bioscience Reports

Commentary on: Calpain-2 participates in the process of calpain-1 inactivation

Article

Author: Kumari, Raniki ; Maiti, Tushar Kanti

AbstractCalpain belongs to the calcium-dependent non-lysosomal cysteine protease. Calpain-1 (C1) and calpain-2 (C2) expression are ubiquitous in mammals and an important mediator of the action of calcium. Specific substrate cleavage by C1 and C2 is critical for several calcium-dependent cellular pathways including neuronal function, muscle contraction, signal transduction, cell differentiation, proliferation, and apoptosis. Research suggests that C1 and C2 perform similar functions due to their structurally highly similar isoforms. Increasing evidence suggests that C1 and C2 carry out their specific function in vivo. A recent paper published by Shinkai-Ouchi et al. (Bioscience Reports (2020) 40, DOI: 10.1042/BSR20200552) elucidated the mechanism to differentiate the function of each calpain with respect to the efficiency and longevity for proteolysis after activation. Further, the study represented that C1 and C2 do not synergistically perform their work in vitro. On the other hand, the activity of C1 is reduced in presence of C2. This insight establishes the platform for future studies to examine how C2 regulates the C1 for substrate proteolysis.

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Calpain1/2

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