Anti-SPR monoclonal antibody

The initiating protease of the complement classical pathway, C1r, represents an upstream and pathway-specific intervention point for complement-related autoimmune and inflammatory diseases. Yet, C1r-targeted therapeutic development is currently underrepresented relative to other complement targets. In this study, we developed a fragment-based drug discovery approach using surface plasmon resonance (SPR) and molecular modeling to identify and characterize novel C1r-binding small-molecule fragments. SPR was used to screen a 2000-compound fragment library for binding to human C1r. This led to the identification of 24 compounds that bound C1r with equilibrium dissociation constants ranging between 160-1700 mu M. Two fragments, termed CMP-1611 and CMP-1696, directly inhibited classical pathway-specific complement activation in a dose-dependent manner. CMP-1611 was selective for classical pathway inhibition, while CMP-1696 also blocked the lectin pathway but not the alternative pathway. Direct binding experiments mapped the CMP-1696 binding site to the serine protease domain of C1r and molecular docking and molecular dynamics studies, combined with C1r autoactivation assays, suggest that CMP-1696 binds within the C1r active site. The group of structurally distinct fragments identified here, along with the structure-activity relationship profiling of two lead fragments, form the basis for future development of novel high-affinity C1r-binding, classical pathway-specific, small-molecule complement inhibitors.

This work is focused on the amplification of green (G), orange (O) and NIR (1.5 mu m) emissions of Er3+ ions by codoping with varying contents (traces <= 0.1 mol%) of Au2O3 in an exotic PbO-B2O3-SeO2 glasses ceramic. The glasses were synthesized by conventional melt quenching method and were crystallized by heat-treating them at crystallization temperature for a period of 24 h. Initial characterization of the samples by means of SEM, XRD, XPS, IR and Raman studies suggested that the post-heated samples are entrenched with poly-crystal grains (with sizes varying from 100 to 500 nm). These studies have also revealed that the concentration of such nanocrystallites is increased with increased content of Au2O3 up to 0.075 mol%. The XRD studies, in particular, have indicated that the glass ceramics are composed of Au-2(SeO3)(2)(SeO4) (crystal phase containing Se ions of mixed valence states) and Au-0 nano particles. The XPS studies have also indicated the presence of Se and gold ions in different valence states in these samples. IR and Raman spectra have suggested increased degree of internal chaos in the glass ceramic with increasing concentration of Au2O3. Optical absorption (OA) spectra of Au2O3 doped glass ceramic samples (without Er3+ ions) exhibited a broad band in the visible region identified as surface plasmon resonance (SPR) band of gold metallic particles. The photoluminescence (PL) spectra of these samples exhibited an emission peak due to inter-band transition from sp to d energy bands of Au-0 metallic particles. This emission is identified to play a crucial role in enhancing PL emission of Er3+ ions in the visible and NIR regions. Finally, we have recorded optical absorption, photoluminescence spectra and decay profiles of the Er3+ doped (with Au2O3 as co-dopant) glass ceramics. The spectra were characterized using J-O theory and different radiative parameters (viz., transition probabilities, branching ratios, radiative lifetime) of green, orange and NIR emission transitions of Er3+ ions were evaluated. The results indicated a significant reinforcement of green (S-4(3/2) -> I-4(5/2)), orange (F-4(9/2) -> I-4(5/2)) and NIR (I-4(13/2) -> I-4(15/2)) emissions of Er3+ ions due to co-doping with Au2O3. Quantitative analysis of the results of PL emission indicated that 0.075 mol% of Au2O3 is the optimal concentration for achieving the highest quantum yield of these three emissions in this glass ceramic. Additional population of 4S(3/2), F-4(9/2) and I-4(13/2) energy levels of Er3+ ions from the excited state of Au-0 metallic particles is found to be the reason for such enhancement of quantum efficiency.