In order to understand whether the ameliorating effect on old ages memory disorder by the root of Salvia miltiorhiza is related to the acetylcholinesterase （ACHE） inhibition, two main ingredients, salvianolic acid B...In order to understand whether the ameliorating effect on old ages memory disorder by the root of Salvia miltiorhiza is related to the acetylcholinesterase （ACHE） inhibition, two main ingredients, salvianolic acid B （1） and rosmarinic acid （2）, which were isolated from S. miltiorhiza water extract, were investigated in vitro by NMR relaxation rate in this work. The results showed that the proton selective relaxation rates and the molecular rotational correlation time of proton pairs for compounds 1 and 2 increased significantly by adding of AChE in mixing solution. The study reveals that the two compounds might bind to the enzyme and have ACHE inhibitory effect, which could contribute to the ameliorating effect at some extent on old ages memory disorder.展开更多
Small GTPases including Ras,Rho,Rab,Arf,and Ran are omnipresent molecular switches in regulating key cellular functions.Their dysregulation is a therapeutic target for tumors,neurodegeneration,cardiomyopathies,and inf...Small GTPases including Ras,Rho,Rab,Arf,and Ran are omnipresent molecular switches in regulating key cellular functions.Their dysregulation is a therapeutic target for tumors,neurodegeneration,cardiomyopathies,and infection.However,small GTPases have been historically recognized as“undruggable”.Targeting KRAS,one of the most frequently mutated oncogenes,has only come into reality in the last decade due to the development of breakthrough strategies such as fragment-based screening,covalent ligands,macromolecule inhibitors,and PROTACs.Two KRAS^(G12C)covalent inhibitors have obtained accelerated approval for treating KRAS^(G12C)mutant lung cancer,and allele-specific hotspot mutations on G12D/S/R have been demonstrated as viable targets.New methods of targeting KRAS are quickly evolving,including transcription,immunogenic neoepitopes,and combinatory targeting with immunotherapy.Nevertheless,the vast majority of small GTPases and hotspot mutations remain elusive,and clinical resistance to G12C inhibitors poses new challenges.In this article,we summarize diversified biological functions,shared structural properties,and complex regulatory mechanisms of small GTPases and their relationships with human diseases.Furthermore,we review the status of drug discovery for targeting small GTPases and the most recent strategic progress focused on targeting KRAS.The discovery of new regulatory mechanisms and development of targeting approaches will together promote drug discovery for small GTPases.展开更多
基金The authors are grateful for supports by the National Natural Science Foundation of China （No. 90409015 and 20473013）.
文摘In order to understand whether the ameliorating effect on old ages memory disorder by the root of Salvia miltiorhiza is related to the acetylcholinesterase （ACHE） inhibition, two main ingredients, salvianolic acid B （1） and rosmarinic acid （2）, which were isolated from S. miltiorhiza water extract, were investigated in vitro by NMR relaxation rate in this work. The results showed that the proton selective relaxation rates and the molecular rotational correlation time of proton pairs for compounds 1 and 2 increased significantly by adding of AChE in mixing solution. The study reveals that the two compounds might bind to the enzyme and have ACHE inhibitory effect, which could contribute to the ameliorating effect at some extent on old ages memory disorder.
基金supported by grants from National Key R&D Program of China(2022YFC2305400,2022YFC3400600)Shenzhen Fundamental Research Program(JCYJ20220530145011025)+1 种基金National Natural ScienceFoundation of China(82282717,82073311)Natural Science Foundation of Sichuan Province(2022JDTD0025)。
文摘Small GTPases including Ras,Rho,Rab,Arf,and Ran are omnipresent molecular switches in regulating key cellular functions.Their dysregulation is a therapeutic target for tumors,neurodegeneration,cardiomyopathies,and infection.However,small GTPases have been historically recognized as“undruggable”.Targeting KRAS,one of the most frequently mutated oncogenes,has only come into reality in the last decade due to the development of breakthrough strategies such as fragment-based screening,covalent ligands,macromolecule inhibitors,and PROTACs.Two KRAS^(G12C)covalent inhibitors have obtained accelerated approval for treating KRAS^(G12C)mutant lung cancer,and allele-specific hotspot mutations on G12D/S/R have been demonstrated as viable targets.New methods of targeting KRAS are quickly evolving,including transcription,immunogenic neoepitopes,and combinatory targeting with immunotherapy.Nevertheless,the vast majority of small GTPases and hotspot mutations remain elusive,and clinical resistance to G12C inhibitors poses new challenges.In this article,we summarize diversified biological functions,shared structural properties,and complex regulatory mechanisms of small GTPases and their relationships with human diseases.Furthermore,we review the status of drug discovery for targeting small GTPases and the most recent strategic progress focused on targeting KRAS.The discovery of new regulatory mechanisms and development of targeting approaches will together promote drug discovery for small GTPases.
