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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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PC-BSA protects against CIA and targets IL-17 and IFNγ responses.Arthritis scores (BSA, n = 7; PC-BSA, n = 6 (A)) and hind paw width (B), expressed as mean scores ±SEM for BSA- or PC-BSA-treatment groups where n =number of individual mice exposed to collagen and disease incidence(C,D), indicated by the % of mice developing a severity score ≥2(C) or ≥4 (D). Serum IL-17 levels are plotted as mean valuesof triplicate IL-17 analyses of serum from individual mice (naïve, n = 3; BSA, n = 6; PC-BSA, n = 6 (E)). (F,G) Exemplar plots of gating strategy of intracellularIL-17 and IFNγ expression by DLN (draining lymph node) cellspooled from BSA- and PC-BSA-treated mice with CIA show CD4 or γδexpression on the x-axis versus cytokine expressionon the y-axis, with the relevant % cytokine positivecells annotated. The numbers of cytokine-expressing CD4+ T cells (H,J), γδ T cells (I,L), and CD8+ T cells (K) present in the pooled DLN cells from the naïve(not exposed to collagen), BSA, and PC-BSA groups are shown. For statisticalanalysis, *p < 0.05.
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fig1: PC-BSA protects against CIA and targets IL-17 and IFNγ responses.Arthritis scores (BSA, n = 7; PC-BSA, n = 6 (A)) and hind paw width (B), expressed as mean scores ±SEM for BSA- or PC-BSA-treatment groups where n =number of individual mice exposed to collagen and disease incidence(C,D), indicated by the % of mice developing a severity score ≥2(C) or ≥4 (D). Serum IL-17 levels are plotted as mean valuesof triplicate IL-17 analyses of serum from individual mice (naïve, n = 3; BSA, n = 6; PC-BSA, n = 6 (E)). (F,G) Exemplar plots of gating strategy of intracellularIL-17 and IFNγ expression by DLN (draining lymph node) cellspooled from BSA- and PC-BSA-treated mice with CIA show CD4 or γδexpression on the x-axis versus cytokine expressionon the y-axis, with the relevant % cytokine positivecells annotated. The numbers of cytokine-expressing CD4+ T cells (H,J), γδ T cells (I,L), and CD8+ T cells (K) present in the pooled DLN cells from the naïve(not exposed to collagen), BSA, and PC-BSA groups are shown. For statisticalanalysis, *p < 0.05.

Mentions: RA hasbeen proposed to exhibit a Th1/Th17 phenotype of autoimmune inflammation,and we have recently shown that ES-62 suppresses both IFNγ andIL-17 production in CIA. While we previously showed that the parasiteproduct modulates Th1 responses by suppression of their priming bydendritic cells (DC24), we found that itsprotective effects against pathogenic IL-17 responses reflect suppressionof a cellular network involving DC, Th17, and γδ T cells.9 Therefore, to address the therapeutic potentialof PC-based SMAs of ES-62 in arthritis, we first determined whethera PC-conjugated protein, PC-BSA, could suppress Th1/Th17 responsesin CIA. Analysis of its effects (relative to BSA) confirmed and extendedour previous findings using PC-ovalbumin (OVA)8 in that PC-BSA suppressed the severity of disease in terms of articularscore (Figure 1A) and hind paw width (Figure 1B) as well as reducing incidence of pathology (Figure 1C), especially that pertaining to high articularscore (Figure 1D; score ≥4). Also, aswith ES-62, PC-BSA reduced the serum levels of IL-17 (Figure 1E), and this was reflected by reduced percentagesand numbers of IL-17-producing CD4+ and γδT cells stimulated with PMA/ionomycin ex vivo (Figure 1F,H,I). Similarly, and also as observed with ES-62, PC-BSAsuppressed IFNγ production by CD4+, CD8+, and γδ T cells (Figure 1G,J–L).Collectively, these data suggested that PC-based SMAs could be a suitablestarting point for the development of novel anti-inflammatory drugsfor RA.


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)

PC-BSA protects against CIA and targets IL-17 and IFNγ responses.Arthritis scores (BSA, n = 7; PC-BSA, n = 6 (A)) and hind paw width (B), expressed as mean scores ±SEM for BSA- or PC-BSA-treatment groups where n =number of individual mice exposed to collagen and disease incidence(C,D), indicated by the % of mice developing a severity score ≥2(C) or ≥4 (D). Serum IL-17 levels are plotted as mean valuesof triplicate IL-17 analyses of serum from individual mice (naïve, n = 3; BSA, n = 6; PC-BSA, n = 6 (E)). (F,G) Exemplar plots of gating strategy of intracellularIL-17 and IFNγ expression by DLN (draining lymph node) cellspooled from BSA- and PC-BSA-treated mice with CIA show CD4 or γδexpression on the x-axis versus cytokine expressionon the y-axis, with the relevant % cytokine positivecells annotated. The numbers of cytokine-expressing CD4+ T cells (H,J), γδ T cells (I,L), and CD8+ T cells (K) present in the pooled DLN cells from the naïve(not exposed to collagen), BSA, and PC-BSA groups are shown. For statisticalanalysis, *p < 0.05.
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fig1: PC-BSA protects against CIA and targets IL-17 and IFNγ responses.Arthritis scores (BSA, n = 7; PC-BSA, n = 6 (A)) and hind paw width (B), expressed as mean scores ±SEM for BSA- or PC-BSA-treatment groups where n =number of individual mice exposed to collagen and disease incidence(C,D), indicated by the % of mice developing a severity score ≥2(C) or ≥4 (D). Serum IL-17 levels are plotted as mean valuesof triplicate IL-17 analyses of serum from individual mice (naïve, n = 3; BSA, n = 6; PC-BSA, n = 6 (E)). (F,G) Exemplar plots of gating strategy of intracellularIL-17 and IFNγ expression by DLN (draining lymph node) cellspooled from BSA- and PC-BSA-treated mice with CIA show CD4 or γδexpression on the x-axis versus cytokine expressionon the y-axis, with the relevant % cytokine positivecells annotated. The numbers of cytokine-expressing CD4+ T cells (H,J), γδ T cells (I,L), and CD8+ T cells (K) present in the pooled DLN cells from the naïve(not exposed to collagen), BSA, and PC-BSA groups are shown. For statisticalanalysis, *p < 0.05.
Mentions: RA hasbeen proposed to exhibit a Th1/Th17 phenotype of autoimmune inflammation,and we have recently shown that ES-62 suppresses both IFNγ andIL-17 production in CIA. While we previously showed that the parasiteproduct modulates Th1 responses by suppression of their priming bydendritic cells (DC24), we found that itsprotective effects against pathogenic IL-17 responses reflect suppressionof a cellular network involving DC, Th17, and γδ T cells.9 Therefore, to address the therapeutic potentialof PC-based SMAs of ES-62 in arthritis, we first determined whethera PC-conjugated protein, PC-BSA, could suppress Th1/Th17 responsesin CIA. Analysis of its effects (relative to BSA) confirmed and extendedour previous findings using PC-ovalbumin (OVA)8 in that PC-BSA suppressed the severity of disease in terms of articularscore (Figure 1A) and hind paw width (Figure 1B) as well as reducing incidence of pathology (Figure 1C), especially that pertaining to high articularscore (Figure 1D; score ≥4). Also, aswith ES-62, PC-BSA reduced the serum levels of IL-17 (Figure 1E), and this was reflected by reduced percentagesand numbers of IL-17-producing CD4+ and γδT cells stimulated with PMA/ionomycin ex vivo (Figure 1F,H,I). Similarly, and also as observed with ES-62, PC-BSAsuppressed IFNγ production by CD4+, CD8+, and γδ T cells (Figure 1G,J–L).Collectively, these data suggested that PC-based SMAs could be a suitablestarting point for the development of novel anti-inflammatory drugsfor RA.

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