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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 suppresses IFNγ and IL-17 responses in CIA.Exemplar plots of gating strategy of intracellular IFNγ (A)and IL-17 (B) expression by DLN cells from representative individualPBS-treated mice with CIA show forward scatter (FSC) or CD4, CD8,and γδ expression on the y-axis versuscytokine expression on the x-axis as indicated. Thenumber of (A) IFNγ-expressing total DLN cells, CD8+ T cells, and CD4+ T cells and (B) IL-17-expressing totalDLN cells, CD4+ T cells, and γδ T cells followingstimulation with PMA/ionomycin from individual mice are shown (naïve, n = 7; PBS, n = 13; 11a, n = 13). For statistical analysis, **p <0.01 and ***p < 0.001.
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fig6: 11a suppresses IFNγ and IL-17 responses in CIA.Exemplar plots of gating strategy of intracellular IFNγ (A)and IL-17 (B) expression by DLN cells from representative individualPBS-treated mice with CIA show forward scatter (FSC) or CD4, CD8,and γδ expression on the y-axis versuscytokine expression on the x-axis as indicated. Thenumber of (A) IFNγ-expressing total DLN cells, CD8+ T cells, and CD4+ T cells and (B) IL-17-expressing totalDLN cells, CD4+ T cells, and γδ T cells followingstimulation with PMA/ionomycin from individual mice are shown (naïve, n = 7; PBS, n = 13; 11a, n = 13). For statistical analysis, **p <0.01 and ***p < 0.001.

Mentions: Our previous work withES-62 showed that it suppressed both IFNγ and IL-17 responses7,9 and hence we investigated whether this was also the case for 11a. Indeed, similarly to ES-62, we found 11a to target IFNγ (Figure 6A) and IL-17(Figure 6B) responses in DLN cells stimulatedwith PMA/ionomycin ex vivo. First, whereas mice with CIA displayedsignificantly higher numbers of DLN, CD8+ T, and CD4+ T cells producing IFNγ in response to PMA/ionomycin-stimulationthan naïve mice, this was not true of the 11a-treated mice exposed to collagen. Moreover, the numbers of IFNγ-expressingcells in the DLN and CD8+ T cell populations were significantlyreduced in the 11a group relative to the PBS-CIA group(Figure 6A). However, no significant differencein IFNγ-producing γδ T cells was found between themice exposed to collagen given 11a or not (results notshown). With respect to IL-17, the effects observed were not as strikingalthough it was still possible to see clear evidence that this pro-inflammatorycytokine was also being targeted. Thus, for example, the numbers ofDLN, CD4+, and γδ T cells were significantlyhigher in PBS, but not 11a, treated mice undergoing CIAthan in mice not exposed to collagen (Figure 6B).


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 suppresses IFNγ and IL-17 responses in CIA.Exemplar plots of gating strategy of intracellular IFNγ (A)and IL-17 (B) expression by DLN cells from representative individualPBS-treated mice with CIA show forward scatter (FSC) or CD4, CD8,and γδ expression on the y-axis versuscytokine expression on the x-axis as indicated. Thenumber of (A) IFNγ-expressing total DLN cells, CD8+ T cells, and CD4+ T cells and (B) IL-17-expressing totalDLN cells, CD4+ T cells, and γδ T cells followingstimulation with PMA/ionomycin from individual mice are shown (naïve, n = 7; PBS, n = 13; 11a, n = 13). For statistical analysis, **p <0.01 and ***p < 0.001.
© Copyright Policy
Related In: Results  -  Collection

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

fig6: 11a suppresses IFNγ and IL-17 responses in CIA.Exemplar plots of gating strategy of intracellular IFNγ (A)and IL-17 (B) expression by DLN cells from representative individualPBS-treated mice with CIA show forward scatter (FSC) or CD4, CD8,and γδ expression on the y-axis versuscytokine expression on the x-axis as indicated. Thenumber of (A) IFNγ-expressing total DLN cells, CD8+ T cells, and CD4+ T cells and (B) IL-17-expressing totalDLN cells, CD4+ T cells, and γδ T cells followingstimulation with PMA/ionomycin from individual mice are shown (naïve, n = 7; PBS, n = 13; 11a, n = 13). For statistical analysis, **p <0.01 and ***p < 0.001.
Mentions: Our previous work withES-62 showed that it suppressed both IFNγ and IL-17 responses7,9 and hence we investigated whether this was also the case for 11a. Indeed, similarly to ES-62, we found 11a to target IFNγ (Figure 6A) and IL-17(Figure 6B) responses in DLN cells stimulatedwith PMA/ionomycin ex vivo. First, whereas mice with CIA displayedsignificantly higher numbers of DLN, CD8+ T, and CD4+ T cells producing IFNγ in response to PMA/ionomycin-stimulationthan naïve mice, this was not true of the 11a-treated mice exposed to collagen. Moreover, the numbers of IFNγ-expressingcells in the DLN and CD8+ T cell populations were significantlyreduced in the 11a group relative to the PBS-CIA group(Figure 6A). However, no significant differencein IFNγ-producing γδ T cells was found between themice exposed to collagen given 11a or not (results notshown). With respect to IL-17, the effects observed were not as strikingalthough it was still possible to see clear evidence that this pro-inflammatorycytokine was also being targeted. Thus, for example, the numbers ofDLN, CD4+, and γδ T cells were significantlyhigher in PBS, but not 11a, treated mice undergoing CIAthan in mice not exposed to collagen (Figure 6B).

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