The development of a targeted and more potent, anti-Inflammatory derivative of colchicine: Implications for gout.
Animals
Anti-Inflammatory Agents
/ therapeutic use
Cells, Cultured
Chemotaxis
/ drug effects
Colchicine
/ analogs & derivatives
Computer Simulation
Drug Design
Gout
/ drug therapy
Humans
Male
Mice
Molecular Docking Simulation
Molecular Targeted Therapy
Neutrophil Activation
/ drug effects
Neutrophils
/ drug effects
Protein Binding
Reactive Oxygen Species
/ metabolism
Tubulin
/ metabolism
Colchicine derivatives
Gout
Inflammation
Neutrophil
Rational drug design
Journal
Biochemical pharmacology
ISSN: 1873-2968
Titre abrégé: Biochem Pharmacol
Pays: England
ID NLM: 0101032
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
05
03
2020
revised:
19
06
2020
accepted:
24
06
2020
pubmed:
1
7
2020
medline:
12
1
2021
entrez:
30
6
2020
Statut:
ppublish
Résumé
Colchicine is routinely used for its anti-inflammatory properties to treat gout and Familial Mediterranean fever. More recently, it was also shown to be of therapeutic benefit for another group of diseases in which inflammation is a key component, namely, cardiovascular disease. Whilst there is considerable interest in repurposing this alkaloid, it has a narrow therapeutic index and is associated with undesirable side effects and drug interactions. We, therefore, developed a derivatives of colchicine that preferentially target leukocytes to increase their potency and diminish their side effects. The anti-inflammatory activity of the colchicine derivatives was tested in experimental models of neutrophil activation by the etiological agent of gout, monosodium urate crystals (MSU). Using a rational drug design approach, the structure of colchicine was modified to increase its affinity for βVI-tubulin, a colchicine ligand preferentially expressed by immune cells. The ability of the colchicine analogues with the predicted highest affinity for βVI-tubulin to dampen neutrophil responses to MSU was determined with in vitro assays that measure MSU-induced production of ROS, release of IL-1 and CXCL8/IL-8, and the increase in the concentration of cytoplasmic calcium. The anti-inflammatory property of the derivatives was assessed in the air pouch model of MSU-induced inflammation in mice. The most effective compound generated, CCI, is more potent than colchicine in all the in vitro assays. It inhibits neutrophil responses to MSU in vitro at concentrations 10-100-fold lower than colchicine. Similarly, in vivo, CCI inhibits the MSU-induced recruitment of leukocytes at a 10-fold lower concentration than colchicine when administered prior to or after MSU. We provide evidence that colchicine can be rendered more potent atinhibiting MSU-induced neutrophil activation and inflammation using a rational drug design approach. The development of compounds such as CCI will provide more efficacious drugs that will not only alleviate gout patients of their painful inflammatory episodes at significantly lower doses than colchicine, but also be of potential therapeutic benefit for patients with other diseases treated with colchicine.
Sections du résumé
BACKGROUND
Colchicine is routinely used for its anti-inflammatory properties to treat gout and Familial Mediterranean fever. More recently, it was also shown to be of therapeutic benefit for another group of diseases in which inflammation is a key component, namely, cardiovascular disease. Whilst there is considerable interest in repurposing this alkaloid, it has a narrow therapeutic index and is associated with undesirable side effects and drug interactions. We, therefore, developed a derivatives of colchicine that preferentially target leukocytes to increase their potency and diminish their side effects. The anti-inflammatory activity of the colchicine derivatives was tested in experimental models of neutrophil activation by the etiological agent of gout, monosodium urate crystals (MSU).
METHODS
Using a rational drug design approach, the structure of colchicine was modified to increase its affinity for βVI-tubulin, a colchicine ligand preferentially expressed by immune cells. The ability of the colchicine analogues with the predicted highest affinity for βVI-tubulin to dampen neutrophil responses to MSU was determined with in vitro assays that measure MSU-induced production of ROS, release of IL-1 and CXCL8/IL-8, and the increase in the concentration of cytoplasmic calcium. The anti-inflammatory property of the derivatives was assessed in the air pouch model of MSU-induced inflammation in mice.
RESULTS
The most effective compound generated, CCI, is more potent than colchicine in all the in vitro assays. It inhibits neutrophil responses to MSU in vitro at concentrations 10-100-fold lower than colchicine. Similarly, in vivo, CCI inhibits the MSU-induced recruitment of leukocytes at a 10-fold lower concentration than colchicine when administered prior to or after MSU.
CONCLUSIONS
We provide evidence that colchicine can be rendered more potent atinhibiting MSU-induced neutrophil activation and inflammation using a rational drug design approach. The development of compounds such as CCI will provide more efficacious drugs that will not only alleviate gout patients of their painful inflammatory episodes at significantly lower doses than colchicine, but also be of potential therapeutic benefit for patients with other diseases treated with colchicine.
Identifiants
pubmed: 32598947
pii: S0006-2952(20)30361-0
doi: 10.1016/j.bcp.2020.114125
pii:
doi:
Substances chimiques
Anti-Inflammatory Agents
0
Reactive Oxygen Species
0
Tubulin
0
Colchicine
SML2Y3J35T
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
114125Subventions
Organisme : CIHR
Pays : Canada
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.