3D-quantitative structure-activity relationship study for the design of novel enterovirus A71 3C protease inhibitors.

A three-dimensional quantitative structure-activity relationships model of enterovirus A71 3C protease inhibitors was constructed in this study. The protein-ligand interaction fingerprint was analyzed to generate a pharmacophore model. A predictive and reliable three-dimensional quantitative structure-activity relationships model was built based on the Flexible Alignment of AutoGPA. Moreover, three novel compounds (I-III) were designed and evaluated for their biochemical activity against 3C protease and anti-enterovirus A71 activity in vitro. III exhibited excellent inhibitory activity (IC50  = 0.031 ± 0.005 µM, EC50  = 0.036 ± 0.007 µM). Thus, this study provides a useful quantitative structure-activity relationships model to develop potent inhibitors for enterovirus A71 3C protease.

Target-guided screening of fragments (TGSOF) in the discovery of inhibitors against EV-A71 3C protease.

Target-guided screening of fragments (TGSOF) was developed and employed in the identification of EV-A71 3C protease (3Cpro) inhibitors. We identified 4-acetylpyridine and 3-acetylpyridine as effective P3 fragments of an inhibitor and obtained the corresponding irreversible inhibitors 12c and 12fvia this method. Furthermore, based on 12c and 12f, we have obtained reversible inhibitors 17c and 17f. These results demonstrated that TGSOF is a useful strategy for identifying suitable fragments in developing leads in drug discovery.

Ursolic Acid, a Natural Nutraceutical Agent, Targets Caspase3 and Alleviates Inflammation-Associated Downstream Signal Transduction.

SCOPE: Ursolic acid (UA) is a pentacyclicterpenoid carboxylic acid that is present in a wide variety of plant foods. There are many beneficial health effects that are attributed to the properties of UA. However, the specific cellular targets of UA and the mechanism underlying downstream signal transduction processes linked to the anti-inflammation pathway have not been thoroughly elucidated to date. METHODS AND RESULTS: Chemical biology strategies such as target fishing, click reaction synthesis of a UA probe and molecular imaging were used to identify potential target proteins of UA. Cysteinyl aspartate specific proteinase 3 (CASP3) and its downstream signaling pathway were verified as potential targets by molecular docking, intracellular enzyme activity evaluation and accurate pathway analysis. The results indicated that UA acted on CASP3, ERK1 and JNK2 targets, alleviated inflammation-associated downstream multiple signal transduction factors, including ERK1, NF-κB and STAT3, and exhibited anti-inflammation activities. CONCLUSION: As a natural dietary supplement, UA demonstrated anti-inflammation activity via inhibition of CASP3 and shows the potential to improve the therapy effect of several inflammation-associated diseases.

Glycosylated Platinum(IV) Complexes as Substrates for Glucose Transporters (GLUTs) and Organic Cation Transporters (OCTs) Exhibited Cancer Targeting and Human Serum Albumin Binding Properties for Drug Delivery.

Glycosylated platinum(IV) complexes were synthesized as substrates for GLUTs and OCTs for the first time, and the cytotoxicity and detailed mechanism were determined in vitro and in vivo. Galactoside Pt(IV), glucoside Pt(IV), and mannoside Pt(IV) were highly cytotoxic and showed specific cancer-targeting properties in vitro and in vivo. Glycosylated platinum(IV) complexes 5, 6, 7, and 8 (IC50 0.24-3.97 µM) had better antitumor activity of nearly 166-fold higher than the positive controls cisplatin (1a), oxaliplatin (3a), and satraplatin (5a). The presence of a hexadecanoic chain allowed binding with human serum albumin (HSA) for drug delivery, which not only enhanced the stability of the inert platinum(IV) prodrugs but also decreased their reduction by reductants present in human whole blood. Their preferential accumulation in cancer cells compared to noncancerous cells (293T and 3T3 cells) suggested that they were potentially safe for clinical therapeutic use.

Inhibition of enterovirus 71 replication by an α-hydroxy-nitrile derivative NK-1.9k.

Enterovirus 71 (EV71) is one of the major etiological agents of human hand-foot-and-mouth disease (HFMD) worldwide. EV71 infection in young children and people with immunodeficiency causes severe symptoms with a high fatality rates. However, there is still no approved drugs to treat such infections. Based on our previous report of a peptide-aldehyde anti-EV71 protease, we present here a highly specific α-hydroxy-nitrile derivative NK-1.9k, which inhibited the proliferation of multiple EV71 strains and coxsackievirus A16 (CVA16) in various cells with EC50 of 37.0 nM with low cytotoxicity (CC50 > 200 µM). The hydroxy-nitrile covalent warhead conferred NK-1.9k high potency and selectivity to interact with the cysteine residue of the active site of the viral protease. We also documented the resistance to NK-1.9k with a N69S mutation in EV71 3Cpro. The combination of NK-1.9k and EV71 polymerase or entry inhibitors produced strong synergistic antiviral effects. Collectively, our findings suggest our compounds can potentially be developed as drugs for the treatment of HFMD.

Discovery of 2'-α-C-Methyl-2'-ß-C-fluorouridine Phosphoramidate Prodrugs as Inhibitors of Hepatitis C Virus.

2'-α-C-Methyl-2'-ß-C-fluorouridine and its phosphoramidate prodrugs were synthesized and evaluated for their inhibitory activity against HCV. The structure-activity relationship analysis of the phosphoramidate moiety found that 17m, 17q, and 17r exhibit potent activities against HCV, with EC50 values of 1.82 ± 0.19, 0.88 ± 0.12, and 2.24 ± 0.22 µM, respectively. The docking study revealed that the recognition of the 2'-ß-F by Arg158, 3'-OH by N291, and the Watson-Crick pairing with the template allowed 23 to form the in-line conformation necessary for its incorporation into the viral RNA chain.

Structure-activity relationship study of peptidomimetic aldehydes as enterovirus 71 3C protease inhibitors.

A series of peptidomimetic aldehydes were designed, synthesized, and evaluated for their biochemical activity against 3C protease (3Cpro) and anti-enterovirus 71 (EV71) activity in vitro. Molecular docking revealed that 5s (IC50 = 0.22 ± 0.07 µM, EC50 = 0.18 ± 0.05 µM) could bind well to the active site of EV71 3Cpro, which was consistent with the biological data compared to reference 5a (IC50 = 0.54 ± 0.02 µM, EC50 = 0.26 ± 0.07 µM). Structure and relationship study led to the discovery of aldehyde 5x (IC50 = 0.10 ± 0.02 µM, EC50 = 0.11 ± 0.07 µM), which exhibited the most potent 3Cpro inhibitory and antiviral activity.

Synthesis and structure-activity relationship of α-keto amides as enterovirus 71 3C protease inhibitors.

α-Keto amide derivatives as enterovirus 71 (EV71) 3C protease (3C(pro)) inhibitors have been synthesized and assayed for their biochemical and antiviral activities. structure-activity relationship (SAR) study indicated that small moieties were primarily tolerated at P1' and the introduction of para-fluoro benzyl at P2 notably improved the potency of inhibitor. Inhibitors 8v, 8w and 8x exhibited satisfactory activity (IC50=1.32±0.26µM, 1.88±0.35µM and 1.52±0.31µM, respectively) and favorable CC50 values (CC50>100µM). α-Keto amide may represent a good choice as a warhead for EV71 3C(pro) inhibitor.