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Initial host-pathogen interactions explained by the Organism Prearranged Recognition Theory: fundamental role of saccharides

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Life Research 2024年第3期7卷 9-23页

作者： Luz P.Blanco Systemic Autoimmunity Branch National Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institute of HealthBethesdaUSA

Herein based on literature available a hypothesis is provided about molecular basis for initial events in establishment *** hypothesis asserts that:"recognition and interaction that occur between organisms is *** are membrane receptors with or without soluble components derived from the respective organisms that bridge specific interactions".Organisms'prearranged recognition theory(OPRT)can be specifically applied to host-microbe interactions where most microbes are coated(opsonised)by soluble components(opsonins)from the host,but there are also some microbes that can bypass host opsonization expressing receptors for the host cells or secreting host’s opsonin-like *** receptors involved in organism's interactions,their specificity and repertoire depend on saccharides from glycoproteins,glycolipids,and polysaccharides(glycans)which are abundant extracellular *** in OPRT is possible to explain species-specific interactions and several other phenomena,such as hyper-infectivity,tissue tropism,differential sensitivity to disease depending on type O-blood,and tumoral cell *** lipid raft domain in cellular membrane is proposed as the main location where interactions will trigger cellular *** scientific and biotechnology applications and alternative routes to modify organism's interactions and consequences are *** is a novel hypothesis regarding the degree to which an organism's interactions are prearranged and the role of saccharides epitopes.

关键词： species-specificity saccharides extracellular-matrix host-pathogen antibodies

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Molecular mechanism underlying the subtype-selectivity of competitive inhibitor NF110 and its distinct potencies in human and rat P2X3 receptors

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Science Bulletin 2018年第24期63卷 1616-1625页

作者： Bin Li Jin Wang Xiaoyang Cheng Yan Liu Yang Yang Xiaona Yang Changrun Guod Youya Niu Peng Cao Xiangyang Lu Michael X.Zhu Yun Tian Ye Yu College of Biosdence and Biotechnology.Hunan Agricultural University Changsha 410128China State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources School of Chemistry and Pharmaceutical ScienceGuangxi Normal UniversityGuilin 541004China Department of Pharmacology and Chemical Biology Institute of Medical SciencesShanghai Jiao Tong University School of MedicineShanghai 200025China School of Basic Medicine and Clinical Pharmacy China Pharmaceutical UniversityNanjing 210009China Department of Cell Biology and Genetics Hunan University of MedicineHuaihua 418000China Hospital of Integrated Traditional Chinese and Western Medicine Nanjing University of Chinese MedicineNanjing 210023China

P2X receptors are a family of extracellular ATP-gated trimeric cation channels that is widely distributed in human tissues. Quite some drug candidates targeting P2X receptors have entered into preclinical or main phases of clinical trials, but many of them failed due to low subtype-selectivity or species differences in pharmacological activities between human and experimental animals. Here, we identified the distinct inhibitory efficacies of NF110, a competitive inhibitor, between the rat(rP2X3) and human(hP2X3) P2X3 receptors. We demonstrated that this difference is determined by two amino acids located in the dorsal fin(DF) domain of P2X3 receptors. As revealed by mutagenesis, metadynamics, and covalent modification, NF110-mediated rP2X3 inhibition may be through a filling in the cavity formed by the DF,left flipper(LF) and lower body(LB) to partially, rather than fully, occupy the ATP-binding ***, substitution of residues located in the DF and/or LF domains of the rP2X2 receptor, a NF110-insensitive subtype, with the equivalent amino acids of rP2X3, bestowed the sensitivity of rP2X2 to NF110. The critical roles of the DF and LF domains in channel gating of P2X and low conservativity in residue sequences of those two domains raise the possibility that small molecules differentially interacting with the residues of the DF and LF domains of different P2X receptors may modulate channel's activity in a subtype-selective manner. However, the possible species-specificity of P2X inhibitors/modulators makes it more complex when interpreting the preclinical data into clinical ***, our data provide new insights into the subtype-selectivity of competitive inhibitors and their distinct potencies in the human and experimental animals, both of which are extremely important in the drug discovery of P2X receptors.

关键词： P2X receptors Competitive inhibitors NF110 species-specificity Subtype-selectivity

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