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: Helminth-based synthetic compound protects against CIA

Lamyaa Al-Riyami, Miguel Pineda, Justyna Rzepecka, Judith Huggan, Abedawn Khalaf, Colin Suckling, David Rodgers, Margaret Harnett, William Harnett, Fraser Scott

Research output: Contribution to journalArticle

50 Citations (Scopus)

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/IL1R transducer, MyD88. (11a) is thus a novel prototype for anti-inflammatory drug development.
LanguageEnglish
Pages9982-10002
Number of pages20
JournalJournal of Medicinal Chemistry
Volume56
DOIs
Publication statusPublished - 2013

Fingerprint

Acanthocheilonema
Experimental Arthritis
Helminths
Anti-Inflammatory Agents
Collagen
Molecules
Phosphorylcholine
Pharmaceutical Preparations
Inbred DBA Mouse
Sulfones
Macrophages
Testing
Transducers
Autoimmune Diseases
Screening
Down-Regulation
Cytokines
Inflammation
Proteins

Keywords

  • arthritis
  • helminth
  • drug development
  • immunomodulation

Cite this

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title = "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: Helminth-based synthetic compound protects against CIA",
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/IL1R transducer, MyD88. (11a) is thus a novel prototype for anti-inflammatory drug development.",
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T1 - 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

T2 - Journal of Medicinal Chemistry

AU - Al-Riyami, Lamyaa

AU - Pineda, Miguel

AU - Rzepecka, Justyna

AU - Huggan, Judith

AU - Khalaf, Abedawn

AU - Suckling, Colin

AU - Rodgers, David

AU - Harnett, Margaret

AU - Harnett, William

AU - Scott, Fraser

PY - 2013

Y1 - 2013

N2 - 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/IL1R transducer, MyD88. (11a) is thus a novel prototype for anti-inflammatory drug development.

AB - 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/IL1R transducer, MyD88. (11a) is thus a novel prototype for anti-inflammatory drug development.

KW - arthritis

KW - helminth

KW - drug development

KW - immunomodulation

UR - http://pubs.acs.org/loi/jmcmar

U2 - 10.1021/jm401251p

DO - 10.1021/jm401251p

M3 - Article

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SP - 9982

EP - 10002

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

ER -