{
  "abstract": "Neutral glucosylceramidase GBA2 is a retaining β-d-glucosidase involved in sphingolipid metabolism and implicated in neurological lysosomal storage disorders, yet the lack of highly selective chemical inhibitors has hindered efforts to disentangle its function from that of glucosylceramide synthase (GCS) and lysosomal glucosylceramidase (GBA1). Here, we report the development of the first brain-penetrant, covalent inhibitor that selectively inactivates GBA2 in vivo. Building on β-d-arabinofuranose-configured (β-d-Araf) cyclitol aziridine activity-based probes previously shown to covalently and selectively label GBA2, we designed and synthesized a focused library of electrophile-bearing cyclitols, including epoxides, cyclic sulfates, and a diverse set of N-alkyl aziridines. Biochemical evaluation of their inhibitory activity against GBA1, GBA2, GBA3 and GCS revealed that several N-alkyl aziridines are highly selective, nanomolar GBA2 inhibitors. Lead compounds also demonstrated metabolic stability in murine plasma, robust cellular activity and high selectivity in living cells, with no detectable GCS inhibition. Notably, octyl-alkyne aziridine 5 selectively inhibited GBA2 in mouse brain, representing the first covalent GBA2 inhibitor with demonstrated in vivo activity and brain permeability. Together, these results establish β-d-Araf cyclitol aziridine 5 as a versatile inhibitor for selective, covalent GBA2 inhibition, well suited to dissect GBA2 biology in vivo, particularly in neurological lysosomal storage disorders.",
  "abstract_shown": true,
  "affiliations": [
    "Departments of Medical Biochemistry and Bio-organic Synthesis, Leiden Institute of Chemistry (LIC), Leiden University , P.O. Box 9502, 2300RA Leiden, The Netherlands.",
    "Departament de Química Inorgànica i Orgànica (Secció de Química Orgànica) and Institut de Química Teòrica i Computacional (IQTCUB), Universitat de Barcelona, Martí i Franquès 1, 08028Barcelona, Spain.",
    "Department of Chemistry, York Structural Biology Laboratory, University of York, Heslington, YorkYO10 5DD, U.K.",
    "Department of Medical Biochemistry, Amsterdam University Medical Center, location Academic Medical Center, University of Amsterdam, Amsterdam1105AZ, The Netherlands.",
    "Amsterdam Gastroenterology, Endocrinology, and Metabolism Institute, Amsterdam University Medical Center, Amsterdam1105AZ, The Netherlands.",
    "Amsterdam Cardiovascular Sciences Institute, Amsterdam University Medical Center, Amsterdam1105AZ, The Netherlands.",
    "Fundació Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010Barcelona, Spain."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 22,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Rob F Lammers"
    },
    {
      "affs": [
        0
      ],
      "name": "Qin Su"
    },
    {
      "affs": [
        1
      ],
      "name": "Laura Mazo"
    },
    {
      "affs": [
        2
      ],
      "name": "Wendy A Offen",
      "orcid": "0000-0002-2758-4531"
    },
    {
      "affs": [
        3
      ],
      "name": "Roelof Ottenhoff"
    },
    {
      "affs": [
        0
      ],
      "name": "Mats J Bulterman"
    },
    {
      "affs": [
        0
      ],
      "name": "Martijn van der Lienden"
    },
    {
      "affs": [
        0
      ],
      "name": "Maria J Ferraz"
    },
    {
      "affs": [
        0
      ],
      "name": "Florian Küllmer",
      "orcid": "0000-0002-0671-1546"
    },
    {
      "affs": [
        0
      ],
      "name": "Zahid Ilhan"
    },
    {
      "affs": [
        0
      ],
      "name": "Hans van den Elst"
    },
    {
      "affs": [
        3
      ],
      "name": "Ingeborg van der Made"
    },
    {
      "affs": [
        3
      ],
      "name": "Cindy P A A van Roomen"
    },
    {
      "affs": [
        0
      ],
      "name": "Anne de Jongh"
    },
    {
      "affs": [
        0
      ],
      "name": "Adrianus M C H van den Nieuwendijk"
    },
    {
      "affs": [
        0
      ],
      "name": "Rolf G Boot"
    },
    {
      "affs": [
        3,
        4,
        5
      ],
      "name": "Noam Zelcer",
      "orcid": "0000-0001-6935-7532"
    },
    {
      "affs": [
        2
      ],
      "name": "Gideon J Davies",
      "orcid": "0000-0002-7343-776X"
    },
    {
      "affs": [
        1,
        6
      ],
      "name": "Carme Rovira",
      "orcid": "0000-0003-1477-5010"
    },
    {
      "affs": [
        0
      ],
      "name": "Herman S Overkleeft",
      "orcid": "0000-0001-6976-7005"
    },
    {
      "affs": [
        0
      ],
      "name": "Johannes M F G Aerts",
      "orcid": "0000-0001-8168-2565"
    },
    {
      "affs": [
        0
      ],
      "name": "Marta Artola",
      "orcid": "0000-0002-3051-3902"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2dkdk3ns23x5y.bib",
  "cited_by": 0,
  "doi": "10.1021/jacs.6c09754",
  "fulltext_url": "https://europepmc.org/articles/PMC13674267",
  "id": "2dkdk3ns23x5y",
  "issns": [
    "0002-7863",
    "1520-5126"
  ],
  "landing_url": "https://europepmc.org/article/MED/42913544",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2737|Lysosomal Storage Disorders Research"
    ]
  ],
  "openalex": "W7214743067",
  "pdf_url": "https://europepmc.org/articles/PMC13674267?pdf=render",
  "pmcid": "PMC13674267",
  "pmid": "42913544",
  "published": "2026-10-01",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2dkdk3ns23x5y.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:14Z",
      "native_id": "MED:42913544",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42913544"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2737|Lysosomal Storage Disorders Research",
      "subfield": "physiology"
    }
  ],
  "title": "β-d-Arabinofuranose-configured Cyclitol Aziridines as Selective, Brain-penetrant Covalent GBA2 Inhibitors.",
  "title_text": "β-d-Arabinofuranose-configured Cyclitol Aziridines as Selective, Brain-penetrant Covalent GBA2 Inhibitors.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:20:14Z",
  "url": "https://research.draconitic.com/paper/2dkdk3ns23x5y",
  "venue": "Journal of the American Chemical Society",
  "versions": []
}