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Designing anti-inflammatory drugs from parasitic worms: a synthetic small molecule analogue of the Acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis.

Al-Riyami L, Pineda MA, Rzepecka J, Huggan JK, Khalaf AI, Suckling CJ, Scott FJ, Rodgers DT, Harnett MM, Harnett W - J. Med. Chem. (2013)

Bottom Line: We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug.Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA).Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development.

View Article: PubMed Central - PubMed

Affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0RE, U.K.

ABSTRACT
In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug. Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA). Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development.

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11a protectsagainst CIA. Disease is shown by eachof mean arthritis score ((A) PBS, n = 13; 11a, n = 13, data pooled from two independent experiments),hind paw width ((B) n = 7, data from a single experiment),and incidence (C,D) indicated by the % of mice developing a severityscore ≥2 ((C) cumulative incidence) or ≥4 ((D) highscore incidence). Results are expressed as mean scores ± SEMfor PBS or 11a-treatment groups of mice exposed to collagen.The numbers of each of total (E), CD4+ (F), CD8+ (G), and γδ (H) T cells in DLN of individual mice fromthe naïve (n = 7), PBS-treated (n = 13) and 11a-treated (n = 13) groups are shown. For statistical analysis, *p < 0.05 and **p < 0.01.
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fig5: 11a protectsagainst CIA. Disease is shown by eachof mean arthritis score ((A) PBS, n = 13; 11a, n = 13, data pooled from two independent experiments),hind paw width ((B) n = 7, data from a single experiment),and incidence (C,D) indicated by the % of mice developing a severityscore ≥2 ((C) cumulative incidence) or ≥4 ((D) highscore incidence). Results are expressed as mean scores ± SEMfor PBS or 11a-treatment groups of mice exposed to collagen.The numbers of each of total (E), CD4+ (F), CD8+ (G), and γδ (H) T cells in DLN of individual mice fromthe naïve (n = 7), PBS-treated (n = 13) and 11a-treated (n = 13) groups are shown. For statistical analysis, *p < 0.05 and **p < 0.01.

Mentions: 11a, at a low dose of ∼50 μg/kgper injection, was tested in the CIA model and it was found that,as with ES-62, it effectively reduced development of arthritis intreated mice. This was reflected in each of disease scores (Figure 5A), hind paw width (Figure 5B), disease incidence (Figure 5C), and percentageof mice with high disease scores (Figure 5D).Moreover, whereas mice with CIA exhibited a significant increase inDLN cell number over the control group not exposed to collagen, thiswas significantly reduced by treatment with 11a (Figure 5E) and to a level not significantly different fromthe control naive group. This result was mirrored by analysis of definedT cell populations, namely CD4+ T cells (Figure 5F), CD8+ T cells (Figure 5G), and γδ T cells (Figure 5H), where 11a-treated mice showed reduced levels ofcells relative to mice with CIA and/or levels not significantly differentto the control group of naive mice not exposed to collagen. Previouslywe had found that CD4+ and γδ T cells fromES-62-treated mice were similarly reduced, although statistical significancehad not been reached.9


Designing anti-inflammatory drugs from parasitic worms: a synthetic small molecule analogue of the Acanthocheilonema viteae product ES-62 prevents development of collagen-induced arthritis.

Al-Riyami L, Pineda MA, Rzepecka J, Huggan JK, Khalaf AI, Suckling CJ, Scott FJ, Rodgers DT, Harnett MM, Harnett W - J. Med. Chem. (2013)

11a protectsagainst CIA. Disease is shown by eachof mean arthritis score ((A) PBS, n = 13; 11a, n = 13, data pooled from two independent experiments),hind paw width ((B) n = 7, data from a single experiment),and incidence (C,D) indicated by the % of mice developing a severityscore ≥2 ((C) cumulative incidence) or ≥4 ((D) highscore incidence). Results are expressed as mean scores ± SEMfor PBS or 11a-treatment groups of mice exposed to collagen.The numbers of each of total (E), CD4+ (F), CD8+ (G), and γδ (H) T cells in DLN of individual mice fromthe naïve (n = 7), PBS-treated (n = 13) and 11a-treated (n = 13) groups are shown. For statistical analysis, *p < 0.05 and **p < 0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4125414&req=5

fig5: 11a protectsagainst CIA. Disease is shown by eachof mean arthritis score ((A) PBS, n = 13; 11a, n = 13, data pooled from two independent experiments),hind paw width ((B) n = 7, data from a single experiment),and incidence (C,D) indicated by the % of mice developing a severityscore ≥2 ((C) cumulative incidence) or ≥4 ((D) highscore incidence). Results are expressed as mean scores ± SEMfor PBS or 11a-treatment groups of mice exposed to collagen.The numbers of each of total (E), CD4+ (F), CD8+ (G), and γδ (H) T cells in DLN of individual mice fromthe naïve (n = 7), PBS-treated (n = 13) and 11a-treated (n = 13) groups are shown. For statistical analysis, *p < 0.05 and **p < 0.01.
Mentions: 11a, at a low dose of ∼50 μg/kgper injection, was tested in the CIA model and it was found that,as with ES-62, it effectively reduced development of arthritis intreated mice. This was reflected in each of disease scores (Figure 5A), hind paw width (Figure 5B), disease incidence (Figure 5C), and percentageof mice with high disease scores (Figure 5D).Moreover, whereas mice with CIA exhibited a significant increase inDLN cell number over the control group not exposed to collagen, thiswas significantly reduced by treatment with 11a (Figure 5E) and to a level not significantly different fromthe control naive group. This result was mirrored by analysis of definedT cell populations, namely CD4+ T cells (Figure 5F), CD8+ T cells (Figure 5G), and γδ T cells (Figure 5H), where 11a-treated mice showed reduced levels ofcells relative to mice with CIA and/or levels not significantly differentto the control group of naive mice not exposed to collagen. Previouslywe had found that CD4+ and γδ T cells fromES-62-treated mice were similarly reduced, although statistical significancehad not been reached.9

Bottom Line: We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug.Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA).Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development.

View Article: PubMed Central - PubMed

Affiliation: Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0RE, U.K.

ABSTRACT
In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases and the continuing identification of defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed from these organisms. We have approached this matter in a novel manner by synthesizing a library of drug-like small molecules based upon phosphorylcholine, the active moiety of the anti-inflammatory Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is unsuitable for use as a drug. Following preliminary in vitro screening for inhibitory effects on relevant macrophage cytokine responses, a sulfone-containing phosphorylcholine analogue (11a) was selected for testing in an in vivo model of inflammation, collagen-induced arthritis (CIA). Testing revealed that 11a was as effective as ES-62 in protecting DBA/1 mice from developing CIA and mirrored its mechanism of action in downregulating the TLR/IL-1R transducer, MyD88. 11a is thus a novel prototype for anti-inflammatory drug development.

Show MeSH
Related in: MedlinePlus