Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

Bligt-Lindén, Eva; Pihlavisto, Marjo; Szatmári, István; Otwinowski, Zbyszek; Smith, David J.; Lázár, László; Fülöp, Ferenc; Salminen, Tiina A.

doi:10.1021/jm401372d

Cited by 29 publications

(37 citation statements)

References 53 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The fact that side chain of a serine is smaller and fits better into the active site cavity of hAOC3 than the large and bulky arginine in the Siglec-9-EC might explain the improved binding properties of the R284S and R290S mutants compared to the WT. It is intriguing that the reversible pyridazinone inhibitors of hAOC3 activity also bind to this unique binding site [47], which now seems to be a physiological binding site as well.…”

Section: Discussionmentioning

confidence: 99%

Multivalent Interactions of Human Primary Amine Oxidase with the V and C22 Domains of Sialic Acid-Binding Immunoglobulin-Like Lectin-9 Regulate Its Binding and Amine Oxidase Activity

et al. 2016

Self Cite

View full text Add to dashboard Cite

Sialic acid-binding immunoglobulin-like lectin-9 (Siglec-9) on leukocyte surface is a counter-receptor for endothelial cell surface adhesin, human primary amine oxidase (hAOC3), a target protein for anti-inflammatory agents. This interaction can be used to detect inflammation and cancer in vivo, since the labeled peptides derived from the second C2 domain (C22) of Siglec-9 specifically bind to the inflammation-inducible hAOC3. As limited knowledge on the interaction between Siglec-9 and hAOC3 has hampered both hAOC3-targeted drug design and in vivo imaging applications, we have now produced and purified the extracellular region of Siglec-9 (Siglec-9-EC) consisting of the V, C21 and C22 domains, modeled its 3D structure and characterized the hAOC3–Siglec-9 interactions using biophysical methods and activity/inhibition assays. Our results assign individual, previously unknown roles for the V and C22 domains. The V domain is responsible for the unusually tight Siglec-9–hAOC3 interactions whereas the intact C22 domain of Siglec-9 is required for modulating the enzymatic activity of hAOC3, crucial for the hAOC3-mediated leukocyte trafficking. By characterizing the Siglec-9-EC mutants, we could conclude that R120 in the V domain likely interacts with the terminal sialic acids of hAOC3 attached glycans whereas residues R284 and R290 in C22 are involved in the interactions with the active site channel of hAOC3. Furthermore, the C22 domain binding enhances the enzymatic activity of hAOC3 although the sialic acid-binding capacity of the V domain of Siglec-9 is abolished by the R120S mutation. To conclude, our results prove that the V and C22 domains of Siglec-9-EC interact with hAOC3 in a multifaceted and unique way, forming both glycan-mediated and direct protein-protein interactions, respectively. The reported results on the mechanism of the Siglec-9–hAOC3 interaction are valuable for the development of hAOC3-targeted therapeutics and diagnostic tools.

show abstract

Section: Discussionmentioning

confidence: 99%

Multivalent Interactions of Human Primary Amine Oxidase with the V and C22 Domains of Sialic Acid-Binding Immunoglobulin-Like Lectin-9 Regulate Its Binding and Amine Oxidase Activity

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…As stated earlier, VAP-1 assists immune cells in traveling to sites of inflammation. When leukocyte migration is mediated by VAP-1, the carbonyl group in VAP-1 is attacked by an amino group in leukocytes (19,20). VAP-1 subsequently acts as a catalyst, and the amino group is transformed to a formyl group.…”

Section: Discussionmentioning

confidence: 99%

“…VAP-1 has the following 2 crucial portions that assist leukocytes in migrating to tissues: a distal adhesion domain and a catalytic amine oxidase portion (19). When immune cells infiltrate sites of inflammation, the amino group in each leukocyte attacks the carbonyl group in VAP-1 (19,20). The primary amine is subsequently converted to the corresponding aldehyde, and this catalytic transformation enables inflammatory cells to squeeze into tissues through blood vessels.…”

mentioning

confidence: 99%

Inhibition of Vascular Adhesion Protein‐1 for Treatment of Graft‐Versus‐Host Disease in Mice

et al. 2018

View full text Add to dashboard Cite

Graft-versus-host disease (GVHD) is a potentially lethal complication of hematopoietic stem cell transplantation (HSCT). GVHD comprises acute and chronic forms. To date, several approaches to treat acute GVHD or chronic GVHD have been reported. However, there is no literature precedent regarding all-in-one methods to address the 2 GVHD types. Severe inflammation in organs affected by GVHD is highly problematic, and vascular adhesion protein-1 (VAP-1) is known to be detrimentally involved in various inflammatory diseases. Based on the previous reports, we envisaged that there would be a link between GVHD and VAP-1, and we strived to create effective therapies for the 2 types of GVHD using a mouse model of GVHD. Our investigation indicated that expression of VAP-1 was elevated in organs disordered by GVHD. Hence, we subsequently attempted to block VAP-1 by using a novel inhibitor. Our results indicate that systemic injection of the inhibitor prevented aberrant influx of inflammatory cells into tissues and thereby mitigate GVHD-elicited inflammation and fibrosis. Collectively, our study suggests that the increased expression of VAP-1 is detrimentally associated with the development of GVHD and that the blockade of VAP-1 could be a promising medical modality to combat the acute and chronic variants.-Mukai, S., Ogawa, Y., Kawakami, Y., Mashima, Y., Tsubota, K. Inhibition of vascular adhesion protein-1 for treatment of graft-versus-host disease in mice.

show abstract

“…For example, the sequences of human and mouse vascular adhesion protein‐1 (hVAP‐1 and mVAP‐1, respectively) are 83% identical . However, pyridazinones, which are potent noncovalently binding, anti‐inflammatory inhibitors designed toward hVAP‐1, do not effectively inhibit the function of the mouse protein . The 3D model of mVAP‐1 successfully explained why the mouse cannot be used as a model organism for the design of inhibitors against hVAP‐1 ( Figure A).…”

Section: Computational Approaches In Molecular Design and Drug Discoverymentioning

confidence: 99%

Tailored Approaches in Drug Development and Diagnostics: From Molecular Design to Biological Model Systems

Sahlgren

Meinander

Zhang

et al. 2017

Adv Healthcare Materials

Self Cite

View full text Add to dashboard Cite

Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic resistance. Development within several areas of research ranging from computational sciences, material sciences, bioengineering to biomedical sciences and bioimaging is needed to realize innovative drug development and diagnostic (DDD) approaches. Here, an overview of recent progresses within key areas that can provide customizable solutions to improve processes and the approaches taken within DDD is provided. Due to the broadness of the area, unfortunately all relevant aspects such as pharmacokinetics of bioactive molecules and delivery systems cannot be covered. Tailored approaches within (i) bioinformatics and computer‐aided drug design, (ii) nanotechnology, (iii) novel materials and technologies for drug delivery and diagnostic systems, and (iv) disease models to predict safety and efficacy of medicines under development are focused on. Current developments and challenges ahead are discussed. The broad scope reflects the multidisciplinary nature of the field of DDD and aims to highlight the convergence of biological, pharmaceutical, and medical disciplines needed to meet the societal challenges of the 21st century.

show abstract

Novel Pyridazinone Inhibitors for Vascular Adhesion Protein-1 (VAP-1): Old Target–New Inhibition Mode

Cited by 29 publications

References 53 publications

Multivalent Interactions of Human Primary Amine Oxidase with the V and C22 Domains of Sialic Acid-Binding Immunoglobulin-Like Lectin-9 Regulate Its Binding and Amine Oxidase Activity

Multivalent Interactions of Human Primary Amine Oxidase with the V and C22 Domains of Sialic Acid-Binding Immunoglobulin-Like Lectin-9 Regulate Its Binding and Amine Oxidase Activity

Inhibition of Vascular Adhesion Protein‐1 for Treatment of Graft‐Versus‐Host Disease in Mice

Tailored Approaches in Drug Development and Diagnostics: From Molecular Design to Biological Model Systems

Contact Info

Product

Resources

About