Imperial College London
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Dr Josefin Ahnström

Faculty of Medicine, Department of Immunology and Inflammation

Senior Lecturer in Haematology
 
 
 
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Contact

 

+44 (0)20 3313 4236j.ahnstrom

 
 
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Location

 

5S5Commonwealth BuildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Santamaria:2021:10.1038/s41598-020-80294-1,
author = {Santamaria, S and Cuffaro, D and Nuti, E and Ciccone, L and Tuccinardi, T and Liva, F and D'Andrea, F and de, Groot R and Rossello, A and Ahnström, J},
doi = {10.1038/s41598-020-80294-1},
journal = {Scientific Reports},
title = {Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide},
url = {http://dx.doi.org/10.1038/s41598-020-80294-1},
volume = {11},
year = {2021}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - ADAMTS-5 is a major protease involved in the turnover of proteoglycans such as aggrecan and versican. Dysregulated aggrecanase activity of ADAMTS-5 has been directly linked to the etiology of osteoarthritis (OA). For this reason, ADAMTS-5 is a pharmaceutical target for the treatment of OA. ADAMTS-5 shares high structural and functional similarities with ADAMTS-4, which makes the design of selective inhibitors particularly challenging. Here we exploited the ADAMTS-5 binding capacity of β-N-acetyl-d-glucosamine to design a new class of sugar-based arylsulfonamides. Our most promising compound, 4b, is a non-zinc binding ADAMTS-5 inhibitor which showed high selectivity over ADAMTS-4. Docking calculations combined with molecular dynamics simulations demonstrated that 4b is a cross-domain inhibitor that targets the interface of the metalloproteinase and disintegrin-like domains. Furthermore, the interaction between 4b and the ADAMTS-5 Dis domain is mediated by hydrogen bonds between the sugar moiety and two lysine residues (K532 and K533). Targeted mutagenesis of these two residues confirmed their importance both for versicanase activity and inhibitor binding. This positively-charged cluster of ADAMTS-5 represents a previously unknown substrate-binding site (exosite) which is critical for substrate recognition and can therefore be targeted for the development of selective ADAMTS-5 inhibitors.
AU  - Santamaria,S
AU  - Cuffaro,D
AU  - Nuti,E
AU  - Ciccone,L
AU  - Tuccinardi,T
AU  - Liva,F
AU  - D'Andrea,F
AU  - de,Groot R
AU  - Rossello,A
AU  - Ahnström,J
DO  - 10.1038/s41598-020-80294-1
PY  - 2021///
SN  - 2045-2322
TI  - Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide
T2  - Scientific Reports
UR  - http://dx.doi.org/10.1038/s41598-020-80294-1
UR  - http://hdl.handle.net/10044/1/86320
VL  - 11
ER  -
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