Abstract:In this study, a highly specific ratiometric two-photon fluorescent probe GP-BAN was developed and well-characterized to monitor dipeptidyl peptidase IV in plasma and living systems. GP-BAN was designed on the basis of the catalytic properties and substrate preference of DPP-IV, and it could be readily hydrolyzed upon addition of DPP-IV under physiological conditions. Both reaction phenotyping and inhibition assays demonstrated that GP-BAN displayed good reactivity and high selectivity towards DPP-IV over othe… Show more
“…Based on the substrate specificities of both CES1 and CES2, some optical probe substrates have been recently developed for assessing the real activities of CES1 or CES2 in complex biological systems ( Supplementary Information Table S2 ) 49 , 51 , 58 , 59 , 60 , 61 , 62 , 63 , 64 . These optical probes provide practical and efficient tools for high-throughput screening (HTS) of CES modulators in cell/tissue preparations or even in living cells, due to the inherent advantages including non-destructive, highly sensitive, easily managed, and applicable to HTS assay 49 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 . Figure 3 Substrate specificity of CES1.…”
Section: Tissue Distribution and Substrate Specificity Of Cesmentioning
Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.
“…Based on the substrate specificities of both CES1 and CES2, some optical probe substrates have been recently developed for assessing the real activities of CES1 or CES2 in complex biological systems ( Supplementary Information Table S2 ) 49 , 51 , 58 , 59 , 60 , 61 , 62 , 63 , 64 . These optical probes provide practical and efficient tools for high-throughput screening (HTS) of CES modulators in cell/tissue preparations or even in living cells, due to the inherent advantages including non-destructive, highly sensitive, easily managed, and applicable to HTS assay 49 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 . Figure 3 Substrate specificity of CES1.…”
Section: Tissue Distribution and Substrate Specificity Of Cesmentioning
Mammalian carboxylesterases (CEs) are key enzymes from the serine hydrolase superfamily. In the human body, two predominant carboxylesterases (CES1 and CES2) have been identified and extensively studied over the past decade. These two enzymes play crucial roles in the metabolism of a wide variety of endogenous esters, ester-containing drugs and environmental toxicants. The key roles of CES in both human health and xenobiotic metabolism arouse great interest in the discovery of potent CES modulators to regulate endobiotic metabolism or to improve the efficacy of ester drugs. This review covers the structural and catalytic features of CES, tissue distributions, biological functions, genetic polymorphisms, substrate specificities and inhibitor properties of CES1 and CES2, as well as the significance and recent progress on the discovery of CES modulators. The information presented here will help pharmacologists explore the relevance of CES to human diseases or to assign the contribution of certain CES in xenobiotic metabolism. It will also facilitate medicinal chemistry efforts to design prodrugs activated by a given CES isoform, or to develop potent and selective modulators of CES for potential biomedical applications.
“…In contrast to non-fluorescent probes, fluorescent substrates for target enzyme(s) have inherent advantages, such as high sensitivity and applicability to HTS 32. , 33.…”
Section: Introductionmentioning
confidence: 99%
“…In contrast to non-fluorescent probes, fluorescent substrates for target enzyme(s) have inherent advantages, such as high sensitivity and applicability to HTS32., 33., 34., 35., 36., 37., 38., 39., 40., 41., 42., 43.. Recently, significant breakthroughs have been made in the development of fluorescent probes for UGT1A1, and several fluorescent probes that are highly selective for UGT1A1 activities in complex biological samples have been successfully developed (Fig.…”
Uridine-diphosphate glucuronosyltransferase 1A1 (UGT1A1) is an important conjugative enzyme in mammals that is responsible for the conjugation and detoxification of both endogenous and xenobiotic compounds. Strong inhibition of UGT1A1 may trigger adverse drug/herb–drug interactions, or result in metabolic disorders of endobiotic metabolism. Therefore, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recommended assaying the inhibitory potential of drugs under development on the human UGT1A1 prior to approval. This review focuses on the significance, progress and challenges in discovery and characterization of UGT1A1 inhibitors. Recent advances in the development of UGT1A1 probes and their application for screening UGT1A1 inhibitors are summarized and discussed in this review for the first time. Furthermore, a long list of UGT1A1 inhibitors, including information on their inhibition potency, inhibition mode, and affinity, has been prepared and analyzed. Challenges and future directions in this field are highlighted in the final section. The information and knowledge that are presented in this review provide guidance for rational use of drugs/herbs in order to avoid the occurrence of adverse effects
via
UGT1A1 inhibition, as well as presenting methods for rapid screening and characterization of UGT1A1 inhibitors and for facilitating investigations on UGT1A1—ligand interactions.
“…In order to further prove the specificity of compound P32 on PL, the selectivity of P32 inhibitory effect was then carried out by a panel of most known serine hydrolase including human carboxylesterase 1 (hCES1A), human carboxylesterase 2 (hCES2A), dipeptidyl peptidase IV (DPP-IV), butyrylcholinesterase (BChE) and thrombin according to the known assays. [23][24][25][26][27][28] As shown in Table 2, compound P32 was found with lower inhibitory effect on hCES1 A (IC 50 , 0.77 μM) and hCES2 A (IC 50 , 6.3 μM) compared with PL (IC 50 , 0.30 μM), and a poor inhibitory effect on BChE, DPP-IV and thrombin with IC 50 values greater than 100. These results indicate that compound P32 is a good inhibitor of PL with some selectivity over other serine hydrolases.…”
Pancreatic lipase (PL), a key target for the prevention and treatment of obesity, plays crucial roles in the hydrolysis and absorption of in dietary fat. In this study, a series of pyrazolones was synthesized, and their inhibitory effects against PL were assayed by using 4-methylumbelliferyl oleate (4-MUO) as optical substrate for PL. Comprehensive structure-activity relationship analysis of these pyrazolones led us to design and synthesize a novel compound P32 (5-(naphthalen-2-yl)-2-phenyl-4-(thiophen-2-ylmethyl)-2,4-dihydro-3H-pyrazol-3-one) as a potent mixed-competitive inhibitor of PL (IC 50 = 0.30 μM). In addition, P32 displayed some selectivity over other known serine hydrolases. A molecular docking study for P32 demonstrated that the inhibitory activity of P32 towards PL could be attributed to the π-π interactions of 2-naphthyl unit (R 1 ) and hydrophobic interactions of phenyl moiety (R 3 ) with the active site of PL. Thus, P32 could serve as promising lead compound for the development of more efficacious and selective pyrazolonestype PL inhibitors for biomedical applications.
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