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As48, a first-in-class dual-function TREM2 modulator: Receptor activation and shedding inhibition
Sungwoo Cho, Farida El Gaamouch, Saurabh Upadhyay, Hossam Nada, Katarzyna Kuncewicz, Moustafa T Gabr. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2025-12-02
Topic: Inflammation, microglia and astrocytes
Triggering receptor expressed on myeloid cells 2 (TREM2) dysfunction contributes to Alzheimer's disease pathogenesis, yet current therapeutics cannot prevent ADAM-mediated receptor shedding that diminishes signaling efficacy. Using Affinity Selection-Mass Spectrometry (AS-MS) screening, we identified As48, a novel small molecule that binds TREM2 with high affinity. Biophysical validation confirmed 7-fold selectivity over TREM1. Cellular assays demonstrated that As48 functions as a TREM2 agonist, activating SYK phosphorylation and enhancing microglial phagocytosis. Molecular docking and molecular dynamics simulations revealed that As48 binds near the cleavage region, establishing hydrogen bonds with Gly68 and reducing conformational flexibility in regions 58-102. Based on this structural insight, we investigated the effect of As48 on TREM2 ectodomain shedding and discovered inhibition of receptor shedding without affecting ADAM10/17 protease activities, representing the first small molecule with anti-shedding properties through conformational restriction of protease accessibility. Importantly, As48 displayed favorable pharmacokinetics with potential for brain permeability, supporting its translational relevance. Through its dual and simultaneous promotion of receptor activation and prevention of shedding, As48 represents a paradigm shift in TREM2 modulation and neuroinflammatory drug discovery.
Key findings
- Cellular assays demonstrated that As48 functions as a TREM2 agonist, activating SYK phosphorylation and enhancing microglial phagocytosis.
- Molecular docking and molecular dynamics simulations revealed that As48 binds near the cleavage region, establishing hydrogen bonds with Gly68 and reducing conformational flexibility in regions 58-102.
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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record, multi-centre collaboration and free to read, so those were left out: it earned 24 of the 56 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41337883) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 24 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 24 of the 56 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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APA 7th
Cho, S., El Gaamouch, F., Upadhyay, S., Nada, H., Kuncewicz, K., & Gabr, M. T. (2025). As48, a first-in-class dual-function TREM2 modulator: Receptor activation and shedding inhibition. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. https://doi.org/10.1016/j.biopha.2025.118862
Vancouver
Cho S, El Gaamouch F, Upadhyay S, Nada H, Kuncewicz K, Gabr MT. As48, a first-in-class dual-function TREM2 modulator: Receptor activation and shedding inhibition. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2025. doi:10.1016/j.biopha.2025.118862. PMID: 41337883.
BibTeX
@article{cho2025-41337883,
author = {Cho, Sungwoo and El Gaamouch, Farida and Upadhyay, Saurabh and Nada, Hossam and Kuncewicz, Katarzyna and Gabr, Moustafa T},
title = {{As48, a first-in-class dual-function TREM2 modulator: Receptor activation and shedding inhibition}},
journal = {Biomedicine \& pharmacotherapy = Biomedecine \& pharmacotherapie},
year = {2025},
doi = {10.1016/j.biopha.2025.118862},
pmid = {41337883},
url = {https://doi.org/10.1016/j.biopha.2025.118862}
}
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