Crystal structures of Triosephosphate Isomerases from Taenia solium and Schistosoma mansoni provide insights for vaccine rationale and drug design against helminth parasites

Abstract

Triosephosphate isomerases (TPIs) from Taenia solium (TsTPI) and Schistosoma mansoni (SmTPI) are potential vaccine and drug targets against cysticercosis and schistosomiasis, respectively. This is due to the dependence of parasitic helminths on glycolysis and because those proteins elicit an immune response, presumably due to their surface localization. Here we report the crystal structures of TsTPI and SmTPI in complex with 2-phosphoglyceric acid (2-PGA). Both TPIs fold into a dimeric (β-α) 8 barrel in which the dimer interface consists of α-helices 2, 3, and 4, and swapping of loop 3. TPIs from parasitic helminths harbor a region of three amino acids knows as the SXD/E insert (S155 to E157 and S157 to D159 in TsTPI and SmTPI, respectively). This insert is located between α5 and β6 and is proposed to be the main TPI epitope. This region is part of a solvent-exposed 3 10 -helix that folds into a hook-like structure. The crystal structures of TsTPI and SmTPI predicted conformational epitopes that could be used for vaccine design. Surprisingly, the epitopes corresponding to the SXD/E inserts are not the ones with the greatest immunological potential. SmTPI, but not TsTPI, habors a sole solvent exposed cysteine (SmTPI-S230) and alterations in this residue decrease catalysis. The latter suggests that thiol-conjugating agents could be used to target SmTPI. In sum, the crystal structures of SmTPI and TsTPI are a blueprint for targeted schistosomiasis and cysticercosis drug and vaccine development. Author summaryBecause of the worldwide prevalence of schistosomiasis and cysticercosis, it is critical to develop drugs and vaccines against their causative agents. The glycolytic enzyme triosephosphate isomerase (TPI) is a dual-edged sword against diseases caused by parasitic helminths. This is because helminths heavily depend on glycolysis for energy and because the PLOS Neglected Tropical Diseases | https://doi.

Candida albicans and Candida glabrata triosephosphate isomerase – a moonlighting protein that can be exposed on the candidal cell surface and bind to human extracellular matrix proteins

“…Moreover, the surface presence of Tpi has also been reported for multicellular parasites such as Taenia solium and Schistosoma mansoni , responsible for cysticercosis and schistosomiasis, respectively. Tpi exposed on the surface of their larvae was suggested to be a potential vaccine and drug target [ 34 – 36 ]. Interestingly, for Staphylococcus aureus , Tpi was suggested to be a potential adhesive molecule involved in the interaction between this bacterium and a fungal pathogen Cryptococcus neoformans via recognition of the skeleton of C. neoformans mannooligosaccharides [ 37 ].…”

Mining gene expression data for rational identification of novel drug targets and vaccine candidates against the cattle tick, Rhipicephalus microplus

“…To further illustrate the hurdle in vaccine development within this space, only a DNA vaccine directed against a Schistosoma japonicum triose-phosphate isomerase (an enzyme traditionally involved in gluconeogenesis), was tested in pigs that resulted in a significant ~ 48% reduction in adult worm burdens in vaccinated pigs (Zhu et al 2006 ). Moreover, this mostly intracellular protein was shown to also be secreted to the surface of the fluke (Jimenez-Sandoval et al 2020 ), therefore, enabling it to elicit an effective host antibody response. For R. microplus, in vitro tick triose-phosphate isomerase (rRmTIM) inhibition assays using murine-derived monoclonal antibodies, demonstrated a high degree of enzyme inhibition (> 48%) (Saramago et al 2012 ).…”

“…(Ortiz et al 2017 ). Such enzymes are also being explored as targets for drug development against helminths (Jimenez-Sandoval et al 2020 ), e.g., Schistosoma mansoni (Hulme et al 2022 ). Therefore, transcripts identified in this study that are related to energy metabolism are considered poor targets for vaccine development, due to the intracellular origin of most of these targets and the concomitant poor extracellular exposure for host immune interactions to confer protection.…”

The Agglomeration of Niacin Crystals in the Cooling Crystallization Process

“…Crystallization technology is one of the most widely applied processes in pharmaceutical purification. [ 1–4 ] It can improve the particle size, crystal habit and product purity of the API crystals. These factors can significantly influence a drug's efficacy, physiological activity and stability.…”