Clickable, selective, and cell-permeable activity-based probe of human cathepsin B - Minimalistic approach for enhanced selectivity

Ashif I Bhuiyan; Pratikkumar Rathod; Sarbani Ghoshal; Dibyendu Dana; Tuhin Das; Guoshen Li; Anna A Dickson; Faiza Rafi; Gopal S Subramaniam; Karl R Fath; Suneeta Paroly; Emmanuel J Chang; Sanjai K Pathak

doi:10.1016/j.bioorg.2021.105463

Clickable, selective, and cell-permeable activity-based probe of human cathepsin B - Minimalistic approach for enhanced selectivity

Bioorg Chem. 2021 Dec:117:105463. doi: 10.1016/j.bioorg.2021.105463. Epub 2021 Nov 2.

Authors

Affiliations

¹ Queens College of The City University of New York, Chemistry and Biochemistry Department, 65-30 Kissena Blvd, Flushing, NY 11367, USA; Chemistry Doctoral Program, The Graduate Center of The City University of New York, 365 5th Ave, New York, NY 10016, USA.
² Laguardia Community College, 31-10 Thomson Ave, Long Island City, NY 11101, USA.
³ Department of Biological Sc. and Geology, QCC-CUNY, Bayside, NY, USA.
⁴ Queens College of The City University of New York, Chemistry and Biochemistry Department, 65-30 Kissena Blvd, Flushing, NY 11367, USA.
⁵ Bard High School Early College Queens, 30-20 Thomson Avenue, Long Island City, NY 11101, USA.
⁶ Queens College of The City University of New York, Department of Biology, 65-30 Kissena Blvd, Flushing, NY 11367, USA; Biochemistry Doctoral Program, The Graduate Center of The City University of New York, 365 5th Ave, New York, NY 10016, USA.
⁷ Biochemistry Doctoral Program, The Graduate Center of The City University of New York, 365 5th Ave, New York, NY 10016, USA; York College of the City University of New York, Department of Chemistry, 94-20 Guy R. Brewer Blvd, Jamaica, NY 11451, USA; Chemistry Doctoral Program, The Graduate Center of The City University of New York, 365 5th Ave, New York, NY 10016, USA.
⁸ Queens College of The City University of New York, Chemistry and Biochemistry Department, 65-30 Kissena Blvd, Flushing, NY 11367, USA; Biochemistry Doctoral Program, The Graduate Center of The City University of New York, 365 5th Ave, New York, NY 10016, USA; Chemistry Doctoral Program, The Graduate Center of The City University of New York, 365 5th Ave, New York, NY 10016, USA. Electronic address: Sanjai.Kumar@qc.cuny.edu.

PMID: 34753058
DOI: 10.1016/j.bioorg.2021.105463

Abstract

Human cathepsin B is a cysteine-dependent protease whose roles in both normal and diseased cellular states remain yet to be fully delineated. This is primarily due to overlapping substrate specificities and lack of unambiguously annotated physiological functions. In this work, a selective, cell-permeable, clickable and tagless small molecule cathepsin B probe, KDA-1, is developed and kinetically characterized. KDA-1 selectively targets active site Cys25 residue of cathepsin B for labeling and can detect active cellular cathepsin B in proteomes derived from live human MDA-MB-231 breast cancer cells and HEK293 cells. It is anticipated that KDA-1 probe will find suitable applications in functional proteomics involving human cathepsin B enzyme.

Keywords: ABP; Activity-based probe; Activity-based probe of cathepsin B; Cathepsin B; Cathepsin B ABP; Cathepsin B probe; Clickable and tagless activity-based probe; Cysteine cathepsins; KDA-1 probe.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cathepsin B / chemistry*
Cathepsin B / genetics
Cell Line
Dose-Response Relationship, Drug
Humans
Molecular Probes / chemical synthesis
Molecular Probes / chemistry*
Molecular Structure
Structure-Activity Relationship

Substances

Molecular Probes
CTSB protein, human
Cathepsin B