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.
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.
Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde , 161 Cathedral Street, Glasgow G4 0RE, U.K.
Lamyaa
L
Al-Riyami
Miguel A
MA
Pineda
Justyna
J
Rzepecka
Judith K
JK
Huggan
Abedawn I
AI
Khalaf
Colin J
CJ
Suckling
Fraser J
FJ
Scott
David T
DT
Rodgers
Margaret M
MM
Harnett
William
W
Harnett
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001168:Arthritis / Q000139:chemically induced / Q000517:prevention & control*; D002478:Cells, Cultured; D003094:Collagen; D015195:Drug Design; D015801:Helminth Proteins / Q000737:chemistry*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; C435884:ES-62 protein, Acanthocheilonema viteae; D015801:Helminth Proteins; D054852:Small Molecule Libraries; D003094:Collagen