Acanthocheilonema

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William Harnett - One of the best experts on this subject based on the ideXlab platform.

  • The parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis.
    Nature communications, 2019
    Co-Authors: James Doonan, Anuradha Tarafdar, Miguel A. Pineda, Felicity E. Lumb, Jenny Crowe, Aneesah M. Khan, Paul A. Hoskisson, Margaret M. Harnett, William Harnett
    Abstract:

    The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Reflecting this, the rapid eradication of pathogens appears to have resulted in reduced microbiome diversity and generation of chronically activated immune systems, presaging the recent rise of allergic, autoimmune and metabolic disorders. Certainly, gastrointestinal helminths can protect against gut and lung mucosa inflammatory conditions by modulating the microbiome and suppressing the chronic inflammation associated with dysbiosis. Here, we employ ES-62, an immunomodulator secreted by tissue-dwelling Acanthocheilonema viteae to show that helminth-modulation of the gut microbiome does not require live infection with gastrointestinal-based worms nor is protection restricted to mucosal diseases. Specifically, subcutaneous administration of this defined immunomodulator affords protection against joint disease in collagen-induced arthritis, a mouse model of rheumatoid arthritis, which is associated with normalisation of gut microbiota and prevention of loss of intestinal barrier integrity.

  • Protection Against Arthritis by the Parasitic Worm Product ES-62, and Its Drug-Like Small Molecule Analogues, Is Associated With Inhibition of Osteoclastogenesis
    Frontiers Media S.A., 2018
    Co-Authors: James Doonan, Anuradha Tarafdar, Miguel A. Pineda, Felicity E. Lumb, Jenny Crowe, Aneesah M. Khan, Margaret M. Harnett, Colin J. Suckling, William Harnett
    Abstract:

    The immunomodulatory actions of parasitic helminth excretory-secretory (ES) products that serendipitously protect against development of chronic inflammatory disorders are well established: however, knowledge of the interaction between ES products and the host musculoskeletal system in such diseases is limited. In this study, we have focused on ES-62, a glycoprotein secreted by the rodent filarial nematode Acanthocheilonema viteae that is immunomodulatory by virtue of covalently attached phosphorylcholine (PC) moieties, and also two synthetic drug-like PC-based small molecule analogues (SMAs) that mimic ES-62’s immunomodulatory activity. We have previously shown that each of these molecules prevents development of pathology in collagen-induced arthritis (CIA), a model of the musculoskeletal disease rheumatoid arthritis (RA) and reflecting this, we now report that ES-62 and its SMAs, modify bone remodeling by altering bone marrow progenitors and thus impacting on osteoclastogenesis. Consistent with this, we find that these molecules inhibit functional osteoclast differentiation in vitro. Furthermore, this appears to be achieved by induction of anti-oxidant response gene expression, thereby resulting in reduction of the reactive oxygen species production that is necessary for the increased osteoclastogenesis witnessed in musculoskeletal diseases like RA

  • Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation
    Experimental parasitology, 2015
    Co-Authors: Lamyaa Al-riyami, Miguel A. Pineda, Margaret M. Harnett, Justyna Rzepecka, David T. Rodgers, Colin J. Suckling, William Harnett
    Abstract:

    ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed.

  • The immunomodulatory parasitic worm product ES-62 reduces lupus-associated accelerated atherosclerosis in a mouse model
    International journal for parasitology, 2015
    Co-Authors: Tamar Aprahamian, Margaret M. Harnett, William Harnett, Lamyaa Al-riyami, Xuemei Zhong, Shahzada Amir, Christoph J. Binder, Lo-ku Chiang, Raffi Gharakhanian, Ian R. Rifkin
    Abstract:

    ES-62 is an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae. Accelerated atherosclerosis frequently occurs in systemic lupus erythematosus, resulting in substantial cardiovascular morbidity and mortality. We examined the effects of ES-62 in the gld.apoE(-/-) mouse model of this condition. Treatment with ES-62 did not substantially modulate renal pathology but caused decreased anti-nuclear autoantibody levels. Moreover, a striking 60% reduction in aortic atherosclerotic lesions was observed, with an associated decrease in macrophages and fibrosis. We believe that these latter findings constitute the first example of a defined parasitic worm product with therapeutic potential in atherosclerosis: ES-62-based drugs may represent a novel approach to control accelerated atherosclerosis in systemic lupus erythematosus.

  • 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
    2015
    Co-Authors: Lamyaa Al-riyami, Margaret M. Harnett, Justyna Rzepecka, David T. Rodgers, Colin J. Suckling, Judith K. Huggan, Abedawn I. Khalaf, Fraser J. Scott, Miguel A. Pineda, William Harnett
    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

R K Chatterjee - One of the best experts on this subject based on the ideXlab platform.

  • Combination Effect of An Immunostimulator (CDRI compound 86/448) and Antifilarial agents on Establishment of Infection
    2016
    Co-Authors: Sunita Bhatnagar, Nigar Fatma, R K Chatterjee
    Abstract:

    Abstract: Effect of two antifilarials ivermectin (microfilaricidal) and CDRI Comp. 82/437 (macrofilaricidal) in combination with immunostimulator (CDRI Comp. 86/448) was evaluated on establishment of Acanthocheilonema viteae infection in Mastomys coucha. The immunostimulator along with the antifilarials was administered on single occasion (Day 0 of larval exposure). Im-munostimulator when given in combination with macrofilaricidal agent (82/437), revealed sig-nificantly less percentage of wormrecovery over untreated control as well as over treated (with either immunostimulator or antifilarial alone) infected controls. It is, thus surmised that estab-lishment of filarial infection is affected by immunostimulant along with antifilarial agent

  • 1 1 dicyano 2 substituted ethylenes a new class of glucose uptake inhibitors in antifilarial chemotherapy
    ChemInform, 2010
    Co-Authors: Swati Tewari, R K Chatterjee, Prem M. S. Chauhan, Amiya Prasad Bhaduri, N. Fatma, Supriya Singh, Vishwa M.l. Srivastava
    Abstract:

    Several 1,1′-dicyano-2-substituted ethylenes (2–16) were synthesized and evaluated for in vivo antifilarial activity. Some of the screened compounds showed significant antifilarial response against Acanthocheilonema viteae in rodents.

  • syntheses and antifilarial profile of 7 chloro 4 substituted amino quinolines a new class of antifilarial agents
    ChemInform, 2000
    Co-Authors: Swati Tewari, Amiya Prasad Bhaduri, Prem M. S. Chauhan, Nigar Fatima, R K Chatterjee
    Abstract:

    The syntheses of 7-chloro-4-(substituted amino) quinolines (2-22) and their antifilarial activities are delineated. Some of the screened compounds have shown promising filarial response and sterilization effect on female Acanthocheilonema viteae in rodents.

  • Antifilarial activity of some 2H-1-benzopyran-2-ones (coumarins).
    Acta tropica, 2000
    Co-Authors: Renu Tripathi, R K Chatterjee, Som Nath Singh, Amiya Prasad Bhaduri, Rama P. Tripathi, P. K. Murthy
    Abstract:

    Six synthetic 2H-1-benzopyran-2-one (cournarin) derivatives (CDRI compounds # 1, 2, 3, 4, 5 and 6) were evaluated for filaricidal activity against Litomosoides carinii and Acanthocheilonema viteae infections in cotton rats (Sigmodon hispidus) and Mastomys coucha respectively. Significant effects on macrofilariae (>80% death/sterilisation) were detected with compounds #2, 3 and 6 against L. carinii and/or A. viteae. Thus detection of filaricidal activity in benzopyrones, which are so far known for anti-inflammatory activity, provides a new lead for development of better filaricidal agents for combating filariasis.

  • Development of in vitro screening system for assessment of antifilarial activity of compounds.
    Acta tropica, 1998
    Co-Authors: Monisha Mukherjee, Shailja Misra, R K Chatterjee
    Abstract:

    Evaluation of antifilarial activity of new potential agents in vivo is extremely time consuming and uneconomic. In the present study effort has been made to develop an in vitro screening method using Acanthocheilonema viteae, a subcutaneously dwelling rodent filariid with anaerobic metabolic characteristics like human filariids, W. Bancrofti/Brugia malayi as test parasite. Motility test and tetrazolium (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, MTT) based colorimetric assay were used as parameters in in vitro assay. Results showed that 92.3% of compounds (in vivo active) could be picked up in the in vitro assay when both adults and microfilarae (mf) were used simultaneously. Mf and adult stages separately detected, respectively, 84.6 and 69.2% of in vivo active compounds. The adults and mf separately and both the life stages together exhibited, respectively, 80.0, 50.0 and 80.0% false positive results in the in vitro test with in vivo inactive compounds. It is felt that mf stage when used in in vitro test using motility and MTT assays as parameters would be useful in primary screening of new potential filaricides.

Heiko Apfel - One of the best experts on this subject based on the ideXlab platform.

  • up regulation of extracellular copper zinc superoxide dismutase mrna after transmission of the filarial parasite Acanthocheilonema viteae in the vertebrate host meriones unguiculatus
    International Journal for Parasitology, 1999
    Co-Authors: Claus T. Lattemann, Arne Matzen, Heiko Apfel
    Abstract:

    Abstract The gene encoding the cytoplasmic copper/zinc superoxide dismutase (AVSOD1) from the filarial parasite Acanthocheilonema viteae was isolated from a genomic DNA library using a degenerate oligonucleotide probe. Additionally, cDNAs of the AVSOD1 and the secreted extracellular SOD (AVSOD2) were both cloned by RT–PCR, and the AVSOD2 was expressed at high levels in E. coli . The amino acid sequence of the AVSOD1 is 89.5 and 87.5% identical to that of the corresponding enzymes of Brugia pahangi and Onchocerca volvulus , respectively. In contrast, the AVSOD2 shows a lower degree of identity to the other filarial SODs and is extensively glycosylated. RT–PCR studies demonstrate the expression of both SOD subtypes in all developmental stages of A. viteae and indicate up-regulation of the AVSOD2 expression after transmission from the vector to the definitive host. This suggests an enhanced requirement for SOD activity in post-infective larval stages and adults of A. viteae . ELISAs performed with purified recombinant AVSOD2 show that the AVSOD2 is not a major target for the immune system in naturally infected jirds.

  • immunogenicity of the extracellular copper zinc superoxide dismutase of the filarial parasite Acanthocheilonema viteae delivered by a two phase vaccine strain of salmonella typhimurium
    Parasite Immunology, 1999
    Co-Authors: Claus T. Lattemann, Thomas F. Meyer, Zhengxin Yan, Arne Matzen, Heiko Apfel
    Abstract:

    The recombinant extracellular copper/zinc superoxide dismutase of the filarial parasite Acanthocheilonema viteae (AVSOD2) was cloned in an expression vector under control of the bacteriophage T7 promoter and the resulting plasmid pLAT7 was introduced in tha aroA attenuated Salmonella typhimurium vaccine strain SL3261::pYZ84. This vaccine strain carries a chromosomally integrated two phase expression system containing inducible T7 RNA polymerase. The recombinant AVSOD2 was efficiently expressed, constituting up to 5% of the total bacterial protein. Furthermore, the plasmid vector containing the AVSOD2 cDNA was shown to be stable over a long period of time in the vaccine strain without antibiotic selection in vitro and in vivo. Jirds which were immunised orally with the recombinant vaccine strain expressing the A. viteae EC-SOD produced a strong humoral immune response.

  • protective immunity linked with a distinct developmental stage of a filarial parasite
    Journal of Immunology, 1994
    Co-Authors: Wilhelm F Eisenbeiss, Heiko Apfel, Thomas F. Meyer
    Abstract:

    Repeated low dose infections of the jird Meriones unguiculatus, with the filarial parasite Acanthocheilonema viteae cause a substantial reduction of the total worm burden, suggesting a parasite-driven immune mechanism that controls super-infections. Quantitative recovery of parasites from tissues of triple infected jirds reveals that the larvae derived from a subsequent challenge infection are inactivated or severely impaired several days after transmission, precisely during their molt from the L3 to the L4 stage. Moreover, only larvae undergoing the molt from L3 to L4 stages are capable of stimulating an immune response directed against the challenge infection, indicating that protective Ag are produced during the molting period. Consistent with this, inactivated L3 or live L4 do not produce the same effect. In contrast to susceptible animals, immune jirds elicit high serum antibody titers against molting Ag. Indirect fluorescence antibody-binding tests with sera from protected jirds reveal specific labeling of the surface of molting L3 and not other larval stages, implying a stage-specific elimination process. The identification of molting L3 as a natural target for host immune mechanisms, emphasizes the central importance of this larval stage for future efforts aimed toward the development of a filarial vaccine.

Margaret M. Harnett - One of the best experts on this subject based on the ideXlab platform.

  • The parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis.
    Nature communications, 2019
    Co-Authors: James Doonan, Anuradha Tarafdar, Miguel A. Pineda, Felicity E. Lumb, Jenny Crowe, Aneesah M. Khan, Paul A. Hoskisson, Margaret M. Harnett, William Harnett
    Abstract:

    The human immune system has evolved in the context of our colonisation by bacteria, viruses, fungi and parasitic helminths. Reflecting this, the rapid eradication of pathogens appears to have resulted in reduced microbiome diversity and generation of chronically activated immune systems, presaging the recent rise of allergic, autoimmune and metabolic disorders. Certainly, gastrointestinal helminths can protect against gut and lung mucosa inflammatory conditions by modulating the microbiome and suppressing the chronic inflammation associated with dysbiosis. Here, we employ ES-62, an immunomodulator secreted by tissue-dwelling Acanthocheilonema viteae to show that helminth-modulation of the gut microbiome does not require live infection with gastrointestinal-based worms nor is protection restricted to mucosal diseases. Specifically, subcutaneous administration of this defined immunomodulator affords protection against joint disease in collagen-induced arthritis, a mouse model of rheumatoid arthritis, which is associated with normalisation of gut microbiota and prevention of loss of intestinal barrier integrity.

  • Protection Against Arthritis by the Parasitic Worm Product ES-62, and Its Drug-Like Small Molecule Analogues, Is Associated With Inhibition of Osteoclastogenesis
    Frontiers Media S.A., 2018
    Co-Authors: James Doonan, Anuradha Tarafdar, Miguel A. Pineda, Felicity E. Lumb, Jenny Crowe, Aneesah M. Khan, Margaret M. Harnett, Colin J. Suckling, William Harnett
    Abstract:

    The immunomodulatory actions of parasitic helminth excretory-secretory (ES) products that serendipitously protect against development of chronic inflammatory disorders are well established: however, knowledge of the interaction between ES products and the host musculoskeletal system in such diseases is limited. In this study, we have focused on ES-62, a glycoprotein secreted by the rodent filarial nematode Acanthocheilonema viteae that is immunomodulatory by virtue of covalently attached phosphorylcholine (PC) moieties, and also two synthetic drug-like PC-based small molecule analogues (SMAs) that mimic ES-62’s immunomodulatory activity. We have previously shown that each of these molecules prevents development of pathology in collagen-induced arthritis (CIA), a model of the musculoskeletal disease rheumatoid arthritis (RA) and reflecting this, we now report that ES-62 and its SMAs, modify bone remodeling by altering bone marrow progenitors and thus impacting on osteoclastogenesis. Consistent with this, we find that these molecules inhibit functional osteoclast differentiation in vitro. Furthermore, this appears to be achieved by induction of anti-oxidant response gene expression, thereby resulting in reduction of the reactive oxygen species production that is necessary for the increased osteoclastogenesis witnessed in musculoskeletal diseases like RA

  • Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation
    Experimental parasitology, 2015
    Co-Authors: Lamyaa Al-riyami, Miguel A. Pineda, Margaret M. Harnett, Justyna Rzepecka, David T. Rodgers, Colin J. Suckling, William Harnett
    Abstract:

    ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed.

  • The immunomodulatory parasitic worm product ES-62 reduces lupus-associated accelerated atherosclerosis in a mouse model
    International journal for parasitology, 2015
    Co-Authors: Tamar Aprahamian, Margaret M. Harnett, William Harnett, Lamyaa Al-riyami, Xuemei Zhong, Shahzada Amir, Christoph J. Binder, Lo-ku Chiang, Raffi Gharakhanian, Ian R. Rifkin
    Abstract:

    ES-62 is an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae. Accelerated atherosclerosis frequently occurs in systemic lupus erythematosus, resulting in substantial cardiovascular morbidity and mortality. We examined the effects of ES-62 in the gld.apoE(-/-) mouse model of this condition. Treatment with ES-62 did not substantially modulate renal pathology but caused decreased anti-nuclear autoantibody levels. Moreover, a striking 60% reduction in aortic atherosclerotic lesions was observed, with an associated decrease in macrophages and fibrosis. We believe that these latter findings constitute the first example of a defined parasitic worm product with therapeutic potential in atherosclerosis: ES-62-based drugs may represent a novel approach to control accelerated atherosclerosis in systemic lupus erythematosus.

  • 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
    2015
    Co-Authors: Lamyaa Al-riyami, Margaret M. Harnett, Justyna Rzepecka, David T. Rodgers, Colin J. Suckling, Judith K. Huggan, Abedawn I. Khalaf, Fraser J. Scott, Miguel A. Pineda, William Harnett
    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

Lamyaa Al-riyami - One of the best experts on this subject based on the ideXlab platform.

  • Protective effect of small molecule analogues of the Acanthocheilonema viteae secreted product ES-62 on oxazolone-induced ear inflammation
    Experimental parasitology, 2015
    Co-Authors: Lamyaa Al-riyami, Miguel A. Pineda, Margaret M. Harnett, Justyna Rzepecka, David T. Rodgers, Colin J. Suckling, William Harnett
    Abstract:

    ES-62 is the major secreted protein of the rodent filarial nematode Acanthocheilonema viteae. The molecule contains covalently attached phosphorylcholine (PC) residues, which confer anti-inflammatory properties on ES-62, underpinning the idea that drugs based on this active moiety may have therapeutic potential in human diseases associated with aberrant inflammation. Here we demonstrate that two synthetic small molecule analogues (SMAs) of ES-62 termed SMA 11a and SMA 12b are protective in the oxazolone-induced acute allergic contact dermatitis mouse model of skin inflammation, as measured by a significant reduction in ear inflammation following their administration before oxazolone sensitisation and before oxazolone challenge. Furthermore, it was found that when tested, 12b was effective at reducing ear swelling even when first administered before challenge. Histological analysis of the ears showed elevated cellular infiltration and collagen deposition in oxazolone-treated mice both of which were reduced by treatment with the two SMAs. Likewise, the oxazolone-induced increase in IFNγ mRNA in the ears was reduced but no effect on other cytokines investigated was observed. Finally, no influence on the mast cell populations in the ear was observed.

  • The immunomodulatory parasitic worm product ES-62 reduces lupus-associated accelerated atherosclerosis in a mouse model
    International journal for parasitology, 2015
    Co-Authors: Tamar Aprahamian, Margaret M. Harnett, William Harnett, Lamyaa Al-riyami, Xuemei Zhong, Shahzada Amir, Christoph J. Binder, Lo-ku Chiang, Raffi Gharakhanian, Ian R. Rifkin
    Abstract:

    ES-62 is an anti-inflammatory phosphorylcholine-containing glycoprotein secreted by the filarial nematode Acanthocheilonema viteae. Accelerated atherosclerosis frequently occurs in systemic lupus erythematosus, resulting in substantial cardiovascular morbidity and mortality. We examined the effects of ES-62 in the gld.apoE(-/-) mouse model of this condition. Treatment with ES-62 did not substantially modulate renal pathology but caused decreased anti-nuclear autoantibody levels. Moreover, a striking 60% reduction in aortic atherosclerotic lesions was observed, with an associated decrease in macrophages and fibrosis. We believe that these latter findings constitute the first example of a defined parasitic worm product with therapeutic potential in atherosclerosis: ES-62-based drugs may represent a novel approach to control accelerated atherosclerosis in systemic lupus erythematosus.

  • 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
    2015
    Co-Authors: Lamyaa Al-riyami, Margaret M. Harnett, Justyna Rzepecka, David T. Rodgers, Colin J. Suckling, Judith K. Huggan, Abedawn I. Khalaf, Fraser J. Scott, Miguel A. Pineda, William Harnett
    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

  • Small molecule analogues of the immunomodulatory parasitic helminth product ES-62 have anti-allergy properties
    International journal for parasitology, 2014
    Co-Authors: Justyna Rzepecka, Lucia Janicova, Lamyaa Al-riyami, Judith K. Huggan, Abedawn I. Khalaf, Michelle L. Coates, Moninder Saggar, Jennifer C. Coltherd, Hwee Kee Tay, Ivonne Siebeke
    Abstract:

    ES-62, a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, exhibits anti-inflammatory properties by virtue of covalently attached phosphorylcholine moieties. Screening of a library of ES-62 phosphorylcholine-based small molecule analogues (SMAs) revealed that two compounds, termed 11a and 12b, mirrored the helminth product both in inhibiting mast cell degranulation and cytokine responses in vitro and in preventing ovalbumin-induced Th2-associated airway inflammation and eosinophil infiltration of the lungs in mice. Furthermore, the two SMAs inhibited neutrophil infiltration of the lungs when administered therapeutically. ES-62-SMAs 11a and 12b thus represent starting points for novel drug development for allergies such as asthma.

  • 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
    Journal of medicinal chemistry, 2013
    Co-Authors: Lamyaa Al-riyami, Miguel A. Pineda, Margaret M. Harnett, Justyna Rzepecka, David T. Rodgers, Colin J. Suckling, Judith K. Huggan, Abedawn I. Khalaf, Fraser J. Scott, William Harnett
    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.