Receptor-interacting serine/threonine-protein kinase 1(RIPK1)functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases.A number of allo...Receptor-interacting serine/threonine-protein kinase 1(RIPK1)functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases.A number of allosteric RIPK1 inhibitors(RIPK1i)have been developed,and some of them have already advanced into clinical evaluation.Recently,selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge.Here,we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i.We also describe the structure-guided lead optimization of a potent,selective,and orally bioavailable RIPK1i,62,which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases.Collectively,62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.展开更多
Electric-dipole optical second harmonic generation(SHG)is a second-order nonlinear process that is widely used as a sensitive probe to detect broken inversion symmetry and local polar order.Analytical modeling of the ...Electric-dipole optical second harmonic generation(SHG)is a second-order nonlinear process that is widely used as a sensitive probe to detect broken inversion symmetry and local polar order.Analytical modeling of the SHG polarimetry of a nonlinear optical material is essential to extract its point group symmetry and the absolute nonlinear susceptibilities.Current literature on SHG analysis involves numerous approximations and a wide range of(in)accuracies.We have developed an open-source package called the Second Harmonic Analysis of Anisotropic Rotational Polarimetry(♯SHAARP.si)which derives analytical and numerical solutions of reflection SHG polarimetry from a single interface(.si)for bulk homogeneous crystals with arbitrary symmetry group,arbitrary crystal orientation,complex and anisotropic linear dielectric tensor with frequency dispersion,a general SHG tensor and arbitrary light polarization.♯SHAARP.si enables accurate modeling of polarimetry measurements in reflection geometry from highly absorbing crystals or wedge-shaped transparent crystals.The package is extendable to multiple interfaces.展开更多
Optical second harmonic generation(SHG)is a nonlinear optical effect widely used for nonlinear optical microscopy and laser frequency conversion.Closed-form analytical solution of the nonlinear optical responses is es...Optical second harmonic generation(SHG)is a nonlinear optical effect widely used for nonlinear optical microscopy and laser frequency conversion.Closed-form analytical solution of the nonlinear optical responses is essential for evaluating materials whose optical properties are unknown a priori.A recent open-source code,♯SHAARP.si,can provide such closed form solutions for crystals with arbitrary symmetries,orientations,and anisotropic properties at a single interface.However,optical components are often in the form of slabs,thin films on substrates,and multilayer heterostructures with multiple reflections of both the fundamental and up to ten different SHG waves at each interface,adding significant complexity.Many approximations have therefore been employed in the existing analytical approaches,such as slowly varying approximation,weak reflection of the nonlinear polarization,transparent medium,high crystallographic symmetry,Kleinman symmetry,easy crystal orientation along a high-symmetry direction,phase matching conditions and negligible interference among nonlinear waves,which may lead to large errors in the reported material properties.To avoid these approximations,we have developed an open-source package named Second Harmonic Analysis of Anisotropic Rotational Polarimetry in Multilayers(♯SHAARP.ml).The reliability and accuracy are established by experimentally benchmarking with both the SHG polarimetry and Maker fringes using standard and commonly used nonlinear optical materials as well as twisted 2-dimensional heterostructures.展开更多
基金We thank Prof.Junying Yuan(IRCBC of CAS,Shanghai,China)and Dr.Jidong Zhu(Etern Therapeutics,Shanghai,China)for their generous help on this work,Dr.Sudan He(ISM of CAMS,Suzhou,China)for providing RIPK3-FKBP NIH/3T3 cells,and National Facility for Protein Science in Shanghai(China)for the help in animal studies.This work was supported by grants from the National Natural Science Foundation of China(Grants Nos.21837004,82151212,and 32170755)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB39050500,China)Shanghai Municipal Science and Technology Major Project(Grant No.2019SHZDZX02,China).
文摘Receptor-interacting serine/threonine-protein kinase 1(RIPK1)functions as a key regulator in inflammation and cell death and is involved in mediating a variety of inflammatory or degenerative diseases.A number of allosteric RIPK1 inhibitors(RIPK1i)have been developed,and some of them have already advanced into clinical evaluation.Recently,selective RIPK1i that interact with both the allosteric pocket and the ATP-binding site of RIPK1 have started to emerge.Here,we report the rational development of a new series of type-II RIPK1i based on the rediscovery of a reported but mechanistically atypical RIPK3i.We also describe the structure-guided lead optimization of a potent,selective,and orally bioavailable RIPK1i,62,which exhibits extraordinary efficacies in mouse models of acute or chronic inflammatory diseases.Collectively,62 provides a useful tool for evaluating RIPK1 in animal disease models and a promising lead for further drug development.
基金This development of the software was supported as part of the Computational Materials Sciences Program funded by the U.S.Department of Energy,Office of Science,Basic Energy Sciences,under Award No.DE-SC0020145R.Z.,B.W.,J.-J.W.,L.-Q.C.,and V.G.were supported by the U.S.Department of Energy,Office of Science,Basic Energy Sciences,under Award No.DE-SC0020145+2 种基金J.H.acknowledges support from National Science Foundation under NSF DMR-2210933L.W.was supported by NSF Research Experiences for Undergraduates(REU),DMR 185-1987Part of this work was performed under the auspices of the U.S.Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344(B.W.).
文摘Electric-dipole optical second harmonic generation(SHG)is a second-order nonlinear process that is widely used as a sensitive probe to detect broken inversion symmetry and local polar order.Analytical modeling of the SHG polarimetry of a nonlinear optical material is essential to extract its point group symmetry and the absolute nonlinear susceptibilities.Current literature on SHG analysis involves numerous approximations and a wide range of(in)accuracies.We have developed an open-source package called the Second Harmonic Analysis of Anisotropic Rotational Polarimetry(♯SHAARP.si)which derives analytical and numerical solutions of reflection SHG polarimetry from a single interface(.si)for bulk homogeneous crystals with arbitrary symmetry group,arbitrary crystal orientation,complex and anisotropic linear dielectric tensor with frequency dispersion,a general SHG tensor and arbitrary light polarization.♯SHAARP.si enables accurate modeling of polarimetry measurements in reflection geometry from highly absorbing crystals or wedge-shaped transparent crystals.The package is extendable to multiple interfaces.
基金supported by the US Department of Energy,Office of Science,Basic Energy Sciences,under Award Number DE-SC0020145 as part of the Computational Materials Sciences Programsupported by the U.S.Department of Energy,Office of Science,Basic Energy Sciences,under Award No.DE-SC0020145+4 种基金J.H.acknowledges support from National Science Foundation under NSF DMR-2210933supported by NSF Research Experiences for Undergraduates(REU),DMR-1851987Part of this work was performed under the auspices of the U.S.Department of Energy by Lawrence Livermore National Laboratory under Contract DE-AC52-07NA27344(B.W.)R.Z.also received support from the NSF MRSEC Center for Nanoscale Science,DMR-2011839,for optical characterizationsfunded by the U.S.Department of Energy(DOE),Office of Science,Basic Energy Sciences under Award Number DE-SC0021118,for the new materials development.
文摘Optical second harmonic generation(SHG)is a nonlinear optical effect widely used for nonlinear optical microscopy and laser frequency conversion.Closed-form analytical solution of the nonlinear optical responses is essential for evaluating materials whose optical properties are unknown a priori.A recent open-source code,♯SHAARP.si,can provide such closed form solutions for crystals with arbitrary symmetries,orientations,and anisotropic properties at a single interface.However,optical components are often in the form of slabs,thin films on substrates,and multilayer heterostructures with multiple reflections of both the fundamental and up to ten different SHG waves at each interface,adding significant complexity.Many approximations have therefore been employed in the existing analytical approaches,such as slowly varying approximation,weak reflection of the nonlinear polarization,transparent medium,high crystallographic symmetry,Kleinman symmetry,easy crystal orientation along a high-symmetry direction,phase matching conditions and negligible interference among nonlinear waves,which may lead to large errors in the reported material properties.To avoid these approximations,we have developed an open-source package named Second Harmonic Analysis of Anisotropic Rotational Polarimetry in Multilayers(♯SHAARP.ml).The reliability and accuracy are established by experimentally benchmarking with both the SHG polarimetry and Maker fringes using standard and commonly used nonlinear optical materials as well as twisted 2-dimensional heterostructures.
