Exosite inhibition of ADAMTS-5 by a glycoconjugated arylsulfonamide

Published on Jan 13, 2021in Scientific Reports3.998
· DOI :10.1038/S41598-020-80294-1
Salvatore Santamaria14
Estimated H-index: 14
(Imperial College London),
Doretta Cuffaro5
Estimated H-index: 5
(UniPi: University of Pisa)
+ 7 AuthorsJosefin Ahnström16
Estimated H-index: 16
(Imperial College London)
Source
Abstract
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.
References50
Newest
A Disintegrin And Metalloproteinase with ThromboSpondin motif (ADAMTS)-5 was identified in 1999 as one of the enzymes responsible for cleaving aggrecan, the major proteoglycan in articular cartilage. Studies in vitro, ex vivo and in vivo have validated ADAMTS-5 as a target in osteoarthritis (OA), a disease characterized by extensive degradation of aggrecan. For this reason, it attracted the interest of many research groups aiming to develop a therapeutic treatment for OA patients. However, ADAMT...
14 CitationsSource
#1Anastasis Petri (Imperial College London)H-Index: 2
#2Hyo Jung Kim (University of Nottingham)H-Index: 2
Last. James T. B. Crawley (Imperial College London)H-Index: 30
view all 9 authors...
Platelet recruitment to sites of blood vessel damage is highly dependent upon von Willebrand factor (VWF). VWF platelet-tethering function is proteolytically regulated by the metalloprotease ADAMTS13. Proteolysis depends upon shear-induced conformational changes in VWF that reveal the A2 domain cleavage site. Multiple ADAMTS13 exosite interactions are involved in recognition of the unfolded A2 domain. Here we report through kinetic analyses that, in binding VWF, the ADAMTS13 cysteine-rich and sp...
20 CitationsSource
#1Salvatore Santamaria (Imperial College London)H-Index: 14
#2Kazuhiro Yamamoto (University of Liverpool)H-Index: 17
Last. Josefin Ahnström (Imperial College London)H-Index: 16
view all 8 authors...
ADAMTS (A Disintegrin-like and Metalloproteinase domain with Thrombospondin type 1 Motif)-1, -4 and -5 share the abilities to cleave large aggregating proteoglycans including versican and aggrecan. These activities are highly relevant to cardiovascular disease and osteoarthritis and during development. Here, using purified recombinant ADAMTS-1, -4 and -5, we quantify, compare, and define the molecular basis of their versicanase activity. A novel sandwich-ELISA detecting the major versican cleava...
11 CitationsSource
#1Salvatore Santamaria (Imperial College London)H-Index: 14
#2Rens de Groot (Imperial College London)H-Index: 9
The metzincin clan of metalloproteinases includes the MMP, ADAM and ADAMTS families, which cleave extracellular targets in a wide range of (patho)physiological processes. Antibodies constitute a powerful tool to modulate the activity of these enzymes for both therapeutic and research purposes. In this review, we give an overview of monoclonal antibodies (mAbs) that have been tested in preclinical disease models, human trials and important studies of metzincin structure and function. Initial atte...
22 CitationsSource
#1Doretta Cuffaro (UniPi: University of Pisa)H-Index: 5
#2Caterina Camodeca (UniPi: University of Pisa)H-Index: 12
Last. Armando Rossello (UniPi: University of Pisa)H-Index: 28
view all 9 authors...
Abstract MMP-12 is a validated target in pulmonary and cardiovascular diseases. The principal obstacles to clinical development of MMP-12 inhibitors are an inadequate selectivity for the target enzyme and a poor water solubility, with consequent poor oral bioavailability. We recently reported a new class of sugar-based arylsulfonamide carboxylates with a nanomolar activity for MMP-12, a good selectivity and an improved water solubility. In this study, we designed and synthesized new derivatives ...
5 CitationsSource
#1Thomas N. Wight (BRI: Benaroya Research Institute)H-Index: 106
Abstract The content of proteoglycans (PGs) is low in the extracellular matrix (ECM) of vascular tissue, but increases dramatically in all phases of vascular disease. Early studies demonstrated that glycosaminoglycans (GAGs) including chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS) and heparan sulfate (HS) accumulate in vascular lesions in both humans and in animal models in areas of the vasculature that are susceptible to disease initiation (such as at branch points) and a...
52 CitationsSource
#1Giulia Bononi (UniPi: University of Pisa)H-Index: 5
#2Carlotta Granchi (UniPi: University of Pisa)H-Index: 24
Last. Tiziano Tuccinardi (UniPi: University of Pisa)H-Index: 35
view all 18 authors...
Abstract Monoacylglycerol lipase (MAGL) is the enzyme hydrolyzing the endocannabinoid 2-arachidonoylglycerol (2-AG) to free arachidonic acid and glycerol. Therefore, MAGL is implicated in many physiological processes involving the regulation of the endocannabinoid system and eicosanoid network. MAGL inhibition represents a potential therapeutic target for many diseases, including cancer. Nowadays, most MAGL inhibitors inhibit this enzyme by an irreversible mechanism of action, potentially leadin...
20 CitationsSource
#1Fabrizio Dal Piaz (UNISA: University of Salerno)H-Index: 30
#2Mariela Beatriz Vera Saltos (ESPE: Escuela Politécnica del Ejército)H-Index: 5
Last. Alessandra BracaH-Index: 31
view all 11 authors...
Five new diterpenes (1–5) and a megastigmane derivative (6) were isolated from the aerial parts of Euphorbia laurifolia, along with several known compounds. Their structures were elucidated by NMR, MS, and ECD and by chemical methods. A chemical proteomics drug affinity responsive target stability (DARTS) approach to investigate the lathyrane diterpene 1, laurifolioside, on its putative cellular target(s) was performed. Clathrin heavy chain 1, a protein mainly involved in selective uptake of pro...
42 CitationsSource
#1Luigi MilellaH-Index: 22
#2Stella Milazzo (UniPi: University of Pisa)H-Index: 3
Last. Alessandra Braca (UniPi: University of Pisa)H-Index: 31
view all 9 authors...
Three new coumarins (1–3), a prenylated flavanone (4), and two iridoids (5 and 6), together with 17 known secondary metabolites, were isolated from the aerial parts of Arcytophyllum thymifolium. The structures of the new compounds were elucidated on the basis of their spectroscopic data. The potential hypoglycemic properties of the new and known compounds were evaluated by measuring their α-amylase and α-glucosidase inhibitory effects. The iridoid asperulosidic acid (15) and the flavonoid rhamne...
51 CitationsSource
#1Elisa Nuti (UniPi: University of Pisa)H-Index: 25
#2Doretta Cuffaro (UniPi: University of Pisa)H-Index: 5
Last. Armando Rossello (UniPi: University of Pisa)H-Index: 28
view all 16 authors...
Matrix metalloproteinase-12 (MMP-12) can be considered an attractive target to study selective inhibitors useful in the development of new therapies for lung and cardiovascular diseases. In this study, a new series of arylsulfonamide carboxylates, with increased hydrophilicity resulting from conjugation with a β-N-acetyl-d-glucosamine moiety, were designed and synthesized as MMP-12 selective inhibitors. Their inhibitory activity was evaluated on human MMPs by using the fluorimetric assay, and a ...
22 CitationsSource
Cited By4
Newest
#1Keron W. J. Rose (ISMMS: Icahn School of Medicine at Mount Sinai)
#2Nandaraj Taye (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 3
Last. Dirk Hubmacher (ISMMS: Icahn School of Medicine at Mount Sinai)H-Index: 19
view all 4 authors...
A disintegrin and metalloprotease with thrombospondin type I motifs (ADAMTS) proteases are secreted metalloproteinases that play key roles in the formation, homeostasis and remodeling of the extracellular matrix (ECM). The substrate spectrum of ADAMTS proteases can range from individual ECM proteins to entire families of ECM proteins, such as the hyalectans. ADAMTS-mediated substrate cleavage is required for the formation, remodeling and physiological adaptation of the ECM to the needs of indivi...
Source
#1Oliver McClurg (UEA: University of East Anglia)
#2Ryan Tinson (UEA: University of East Anglia)H-Index: 4
Last. Linda Troeberg (UEA: University of East Anglia)H-Index: 28
view all 3 authors...
Osteoarthritis is a common, degenerative joint disease with significant socio-economic impact worldwide. There are currently no disease-modifying drugs available to treat the disease, making this an important area of pharmaceutical research. In this review, we assessed approaches being explored to directly inhibit metalloproteinase-mediated cartilage degradation and to counteract cartilage damage by promoting growth factor-driven repair. Metalloproteinase-blocking antibodies are discussed, along...
Source
#1Jess Pedrina (Deakin University)
#2John Stambas (Deakin University)H-Index: 24
Each year, hundreds of thousands of individuals succumb to influenza virus infection and its associated complications. Several preventative and therapeutic options may be applied in order to preserve life. These traditional approaches include administration of seasonal influenza vaccines, pharmacological interventions in the form of antiviral drug therapy and supportive clinical approaches including mechanical ventilation and extracorporeal membrane oxygenation. While these measures have shown v...
Source
#1Lejian Jiang (ZJU: Zhejiang University)
#2Jiachen Lin (Peking Union Medical College Hospital)H-Index: 3
Last. Lin Mao (ZJU: Zhejiang University)
view all 10 authors...
Source