Increasing evidences suggest that the type I interferon (IFN) plays a critical role in the etiopathogenesis of systemic lupus erythematosus (SLE), which makes it a promising therapeutic target for the treatment of the disease. By screening a large size non-immune human antibody library, we have developed a human single-chain antibody (ScFv) AIFNα1bScFv01 and corresponding whole antibody AIFNα1bIgG01, that recognizes recombinant human interferon alpha1b (hIFNα1b) with high specificity and high affinity. The IgG antibody can downregulate the expression of ISG15 and IFIT-1 induced by either recombinant hIFNα1b or naive IFN-α presented in SLE patient's sera. The crystal structure of AIFNα1bScFv01-hIFNα1b complex solved to 2.8 Å resolution reveals that both Pro26-Gln40 region in loop AB and Glu147-Arg150 region in helice E of hIFNα1b contribute to binding with AIFNα1bScFv01. Four residues of above two regions (Leu30, Asp32, Asp35 and Arg150) are critical for the formation of antigen-antibody complexes. AIFNα1bScFv01 shares partial epitopes of IFNα1b with its receptor IFNAR2. AIFNα1bIgG01 has a much higher affinity for IFNα1b than IFNAR2 (K D = 0.747 nM versus 100 nM), making it unavailable for binding to IFNAR2 and preventing the activation of IFN-α-mediated signaling pathway. Thus, AIFNα1bIgG01 exhibits its neutralizing activity through competition with IFNRA2 to bind with IFN-α. Our results highlight the potential use of the human antibody for modulating the activity of IFN-α in SLE. Type-2 diabetes mellitus (T2DM) accounts for more than 90% of all diabetes worldwide. Over 100 million people worldwide have T2DM, and the prevalence is increasing dramatically in both the developed and developing countries. Amyloid deposits have been observed in a vast majority of the T2DM patients and these are primarily on account of misfolding and aggregation into fibrils of human islet amyloid polypeptide (hIAPP), a 37 residue endocrine hormone secreted by pancreatic β-cells. It has been suggested that intermediates produced in the process of fibrillization are cytotoxic to insulin producing β-cells. Hence, the inhibition of misfolding/fibrillization of hIAPP could be a possible strategy to mitigate T2DM. The misfolding of hIAPP involves structural transition from its native state (coil and/or helical and/or transient helical conformation) to β-sheet conformation. We have targeted hIAPP fibrillization by designing short peptides containing the helix inducing α,β-dehydrophenylalanine (∆Phe or ΔF) amino acid and the fibrillization inhibition was monitored by thioflavin-T assay and electron microscopy. We find that the short peptides inhibit fibrillization without any cytotoxic effect as tested on RIN4fm pancreatic cell line. Of these, the penta-peptide, FGA∆FL is the most effective inhibitor of hIAPP fibrillization. We successfully crystallized the penta-peptide and solved its 3D structure at atomic resolution using direct methods. Molecular conformation of the peptide reveals the occurrence of a nest-motif (Fig. A) involving the st...
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