Ethics

Ethics & Compliance Reviewer

SCORE: 5 CONFIDENCE: 5

Summary

This manuscript describes an activity-based protein profiling (ABPP) platform for mapping covalent ligandability in primary mouse brain cells and applies it to discover allosteric modulators of HCN channels. The ethics and compliance framework is sound. All required statements for animal research, funding, and competing interests are present and clearly disclosed. No human subjects, clinical data, or restricted-consent materials are involved. The work is exempt from human subjects review on its face.

Compliance Status

Animal research: Approved. The manuscript states "All experiments were performed in compliance with protocols approved by The Scripps Research Institute Institutional Review Board" and separately notes that Columbia University experiments "were conducted in accordance with policies of the NIH Guide for the Care and Use of Laboratory Animals and the Institutional Animal Care and Use Committee (IACUC) of Columbia University." Both institutions and their IACUC oversight are named. The age and sex of animals used are specified throughout (e.g., "Male 4–8 week old WT C57BL/6 mice"). Housing and care standards are documented.

Funding and competing interests: Fully disclosed. The Acknowledgements section names specific funding sources (Claudia Skaggs Luttrell Endowed Fellowship, Lundbeck La Jolla Research Center, Toni Rosenberg Memorial Fellowship). The Declaration of Interests section explicitly states: "B.F.C. is an advisor to Vividion Therapeutics and a scientific advisor to Lundbeck. C.L.H. and J.L.B. are employees of Lundbeck La Jolla Research Center. G.S.M. is an employee of Vividion Therapeutics." These relationships are material and appropriately flagged.

Data availability: Proteomics data are deposited in ProteomeXchange (PXD082934) with a public repository link. Materials are available from the lead contact under a Materials Transfer Agreement, which is standard practice for chemical probes.

Human subjects and identifiable data: Not applicable. No human subjects, patient data, or identifiable information are present.

Dual-use or biosafety risk: Not applicable. The work is chemical proteomics and electrophysiology; no pathogen engineering, gain-of-function research, or dual-use concern is present.

Strengths

1. Competing interests involving both Lundbeck (a funder) and Vividion are transparently declared, allowing readers to weigh potential bias in target selection and interpretation.

2. Animal protocols are named with institutional oversight at two independent sites, and housing/care standards are documented to a level that supports reproducibility.

3. Data deposition in a public repository with a specific accession number meets the standard for verifiability.

Weaknesses

None identified. All required compliance statements are present, specific, and internally consistent. No contradictions between methods and approvals. No silence on triggered categories.

Questions

None.