Small molecule analogues of the immunomodulatory parasitic helminth product ES-62 have anti-allergy properties

Abstract

ES-62, a glycoprotein secreted by the filarial nematode Acanthocheilonema viteae, exhibits anti-inflamma-tory 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 eosin- ophil 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

Novel therapeutic compound tuftsin–phosphorylcholine attenuates collagen-induced arthritis

“…Harnett et al . designed a sulphone‐containing PC analogue (11a,12b) and provided proof of concept to the therapeutic capabilities of small molecule analogues in mice with CIA model .…”

“…The quest for a drug that possesses beneficial immunomodulation capabilities, as do helminthes, to enable novel treatment approaches in autoimmunity with low side effects led to the creation of small immunomodulating molecules. Harnett et al designed a sulphone-containing PC analogue (11a,12b) and provided proof of concept to the therapeutic capabilities of small molecule analogues in mice with CIA model [35,36].…”

Parasitic Infection and Immunomodulation: A Possible Explanation for the Hygiene Hypothesis in Autoimmune and Allergic Disease

“…28 Aside from administering the parasitic agents themselves as therapy for allergic or inflammatory diseases, a proposed alternative modality is the administration of therapeutic agents which are based upon secreted parasitic glycoproteins such as ES-62. 29,30 However, the therapeutic applicability of such products is limited by large molecular size of these a p o l l o m e d i c i n e 1 1 ( 2 0 1 4 ) 1 9 7 e2 0 0 proteins and their potential immunogenicity, which may be overcome through the development of small molecule analogues which are currently under evaluation and show promise in mouse models. 30 …”

“…29,30 However, the therapeutic applicability of such products is limited by large molecular size of these a p o l l o m e d i c i n e 1 1 ( 2 0 1 4 ) 1 9 7 e2 0 0 proteins and their potential immunogenicity, which may be overcome through the development of small molecule analogues which are currently under evaluation and show promise in mouse models. 30 …”

Alzheimer's disease vaccine development: A new strategy focusing on immune modulation

“…In effect, adjuvants that stimulate Th2-only immunity, are rare and related to compounds like phosphorylated choline derivatives and fucosylated glycans, which are found in both mammals and parasitic helminths (Harnett and Harnett, 2006;Marciani, 2014a). A well known immunomodulator from parasitic worms is the glycoprotein ES-62, which owes its anti inflammatory properties to the phosphorylcholine (PC) groups attached to its glycans (Al-Riyami and Harnett, 2012;Rzepcka et al, 2014). Indeed, PC is responsible for the immune modulatory effects of sphingosine-1-phosphate (S1P), which is produced by phosphorylation of sphingolipids by two sphingoside kinases and is essential for immune-cell trafficking; i.e., S1P favors Th2 and Th17, while dampening Th1 immunoresponses (Rivera et al, 2008).…”