2026-10-12T20:42:29Z https://api.figshare.com/v2/oai

oai:figshare.com:article/34033433 2026-09-30T15:20:54Z category_1 category_4 category_13 category_14 category_19 category_21 category_873 category_46 category_734 category_64 category_132 portal_63 item_type_3 month_year_09_2026

Ninhydrin as a Covalent Warhead for Chemical Proteomic-Enabled Discovery and Selective Engagement of Reactive Arginines Andrew K. Ecker (12602573) Andreas Langen (4234192) Chloe S. Fields (25144664) José L. Montaño (25144667) Minh Tran (7698803) Ian B. Seiple (2079991) Balyn W. Zaro (558018) Biophysics Biochemistry Genetics Molecular Biology Pharmacology Biotechnology Chemical Sciences not elsewhere classified Immunology Biological Sciences not elsewhere classified Cancer Infectious Diseases amino acids targetable scale arginines amenable one cell line studying arginine reactivity molecule discovery pipelines chemical proteomic methods findings establish ninhydrin chemical proteomic reactive arginines molecule binder enabled discovery cell lysates vitro </ transformed small thus expanding selective engagement reversible small relevant proteins reactive cysteines powerful tools generation therapeutics functionalized variants enzymatic activity developed alkyne covalent molecules covalent modification covalent engagement achieved selective Covalent molecules have emerged as next-generation therapeutics and as powerful tools for perturbing fundamental biological processes. Chemical proteomic methods to screen for reactive proteinaceous amino acids have transformed small-molecule discovery pipelines, but their application remains mostly limited to sites where reactive cysteines and lysines are present. Here we report a ninhydrin-based warhead that selectively modifies arginine residues, thus expanding the repertoire of amino acids targetable by covalent molecules. Specifically, we developed alkyne-functionalized variants of ninhydrin to establish an arginine-specific chemical proteomics platform, enabling the classification of more than 6,800 unique reactive arginines from one cell line. These studies uncovered potential modification sites on disease-relevant proteins, including reactive arginines within catalytic sites that are essential for function and reactive arginines on proteins lacking reactive cysteines. By endowing a reversible small-molecule binder of cyclophilin A with a ninhydrin warhead, we achieved selective, covalent engagement in cell lysates and attenuation of enzymatic activity <i>in vitro</i>. These findings establish ninhydrin as a warhead for studying arginine reactivity and identifying at scale arginines amenable to covalent modification. 2026-09-30T00:00:00Z Dataset Dataset 10.1021/acscentsci.6c00922.s002 https://figshare.com/articles/dataset/Ninhydrin_as_a_Covalent_Warhead_for_Chemical_Proteomic-Enabled_Discovery_and_Selective_Engagement_of_Reactive_Arginines/34033433 CC BY-NC 4.0