Danny Chou, Postdoctoral Faculty Sponsor
- A cysteine-specific solubilizing tag strategy enables efficient chemical protein synthesis of difficult targets CHEMICAL SCIENCE 2024
Bmk9 and Uricase Nanoparticle Complex for the Treatment of Gouty Arthritis and Uric Acid Nephropathy.
Journal of biomedical nanotechnology
2021; 17 (10): 2071-2084
Uric acid is the final product of purine metabolism, and excessive serum uric acid can cause gouty arthritis and uric acid nephropathy. Therefore, lowering the uric acid level and alleviating inflammation in the body are the key points to treating these diseases. A stable nanosuspension of peptide BmK9 was prepared by the precipitation-ultrasonication method. By combining uricase on the surface of a positively charged carrier, a complex consisting of neutral rod-shaped BmK9 and uricase nanoparticles (Nplex) was formed to achieve the delivery of BmK9 and uricase, respectively. The formulation of Nplex has a diameter of 180 nm and drug loading up to 200%, which releases BmK9 and uricase slowly and steadily in drug release tests in vitro. There was significantly improved pharmacokinetic behavior of the two drugs because Nplex prolonged the half-life and increased tissue accumulation. Histological assessments showed that the dual drug Nplex can reduce the inflammation response in acute gouty arthritis and chronic uric acid nephropathy in vivo. In the macrophage system, there was lower toxicity and increased beneficial effect on inflammation with Nplex than free BmK9 or uricase. Collectively, this novel formulation provides a dual drug delivery system that can treat gouty arthritis and uric acid nephropathy.
View details for DOI 10.1166/jbn.2021.3168
View details for PubMedID 34706807
Identification of poly(ADP-ribose)polymerase 1 and 2 (PARP1/2) as targets of andrographolide using an integrated chemical biology approach.
Chemical communications (Cambridge, England)
2021; 57 (51): 6308-6311
Here, we describe the identification of PARP1/2 as direct binding proteins of andrographolide (Andro) using protein microarray, surface plasmon resonance (SPR), and enzyme activity assays. We then evaluated the proliferation inhibition, apoptosis, and cell migration effects of Andro on the MDA-MB-436 cell line in vitro. The final biological evaluation confirmed that Andro was a highly effective single agent in the MDA-MB-436 xenograft model and had a low hERG-mediated cardiac toxicity. Therefore, Andro represents the first natural product, non-amide member of a novel nanomolar-potency PARP1/2 inhibitor family.
View details for DOI 10.1039/d1cc02272e
View details for PubMedID 34075974
Discovery of Novel and Potent N-Methyl-d-aspartate Receptor Positive Allosteric Modulators with Antidepressant-like Activity in Rodent Models.
Journal of medicinal chemistry
2021; 64 (9): 5551-5576
N-Methyl-d-aspartate receptors (NMDARs) are glutamate-gated Na+ and Ca2+-permeable ion channels involved in excitatory synaptic transmission and synaptic plasticity. NMDAR hypofunction has long been implicated in the pathophysiology including major depressive disorders (MDDs). Herein, we report a series of furan-2-carboxamide analogues as novel NMDAR-positive allosteric modulators (PAMs). Through structure-based virtual screen and electrophysiological tests, FS2921 was identified as a novel NMDAR PAM with potential antidepressant effects. Further structure-activity relationship studies led to the discovery of novel analogues with increased potentiation. Compound 32h caused a significant increase in NMDAR excitability in vitro and impressive activity in the forced swimming test. Moreover, compound 32h showed no significant inhibition of hERG or cell viability and possessed a favorable PK/PD profile. Our study presented a series of novel NMDAR PAMs and provided potential opportunities for discovering of new antidepressants.
View details for DOI 10.1021/acs.jmedchem.0c02018
View details for PubMedID 33934604
Isolation and characterization of ent-pimarane diterpenoids from Sigesbeckia pubescens.
Natural product research
2021; 35 (9): 1510-1517
Five new ent-pimarane diterpenoids ent-16-nor-2-oxopimar-8(14)-ene-15,19-dial (1), ent-16-nor-2α,19-dihydroxypimar-8-en-15-al (2), 3-O-acetyldarutigenol (3), 19-O-acetylkirenol (4), ent-16-nor-3β,15-dihydroxypimar-8(14)-ene (5) were isolated and characterized from the ethanol extract of Sigesbeckia pubescens. Their structures were elucidated on the basis of spectroscopic analysis. The absolute configuration of C-15 in compounds 3 and 4 was assigned using Snatzke's method. All these compounds were assessed for their anti-inflammatory potential by measuring the inhibitory effects on NO production in LPS-induced RAW 264.7 macrophage cells and compound 4 showed significantly inhibitory activity with IC50 value of 5.9 μM.
View details for DOI 10.1080/14786419.2019.1656627
View details for PubMedID 31502473
Synthesis and biological evaluation of Isosteviol derivatives as FXa inhibitors.
Bioorganic & medicinal chemistry letters
2020; 30 (2): 126585
Firstly, a series of Isosteviol derivatives were synthesized and evaluated for FXa inhibitory activity. Among these compounds, the inhibitory activity of compounds 22, 35 and 38 on FXa was better than that of Isosteviol. Secondly, surface plasmon resonance (SPR) assays were performed for selected compounds. Compounds 22, 35, 38 have similar kinetic signatures, and affinity values were at μM level. Thirdly, compounds 22 and 35 displayed moderate-to-high anticoagulation activity and showed similar sensitivity to PT and aPTT. These findings will provide new insight into the exploration of FXa inhibition.
View details for DOI 10.1016/j.bmcl.2019.07.044
View details for PubMedID 31859158
Synthesis and biological evaluation of Vinpocetine derivatives.
Bioorganic & medicinal chemistry letters
2020; 30 (2): 126472
A new series of Vinpocetine derivatives were synthesized and evaluated for their inhibitory activity on PDE1A in vitro. Seven compounds with higher inhibitory activity were selected for surface plasmon resonance (SPR) binding experiments. Compared with Vinpocetine, these high potency compounds presented a higher binding affinity with PDE1A, which was consistent with inhibitory activity. After further screening, compounds 5, 7, 21, 34 and Vinpocetine were selected to examine the vasorelaxant effects on endothelium-intact rat thoracic aortic rings. The study suggested that the effects of compounds 7 and 21 were the most significant with the maximum value of 93.46 ± 0.77% and 92.90 ± 0.78% (n = 5) at a concentration of 100 μM respectively. Based on these studies, compounds 7 and 21 were considered for further development as hit compounds.
View details for DOI 10.1016/j.bmcl.2019.05.052
View details for PubMedID 31859156
Synthesis and biological evaluation of panaxatriol derivatives against myocardial ischemia/reperfusion injury in the rat.
European journal of medicinal chemistry
2020; 185: 111729
Panaxatriol (PT) is a natural product derived from ginseng that possesses cardioprotective effects in isolated rat hearts. To develop more potent therapeutic agents against myocardial ischemia/reperfusion (MI/R) injury from natural products, a novel series of heterocycle ring-fused panaxatriol derivatives were designed and synthesized. In vitro results showed that approximately half of them exhibited increased cytoprotective activity compared with PT in a cardiomyocyte model of oxygen-glucose deprivation and reperfusion (OGD/R) injury. Furthermore, the in vitro activity of the representative derivative, compound 18, was also confirmed in a rat model of MI/R injury. In vivo results showed that 18 can markedly reduce myocardial infarction size, decrease circulating cardiac troponin I (cTnI) leakage, and alleviate cardiac tissue damage in the rats. Therefore, these findings provide the basis for further development of novel anti-MI/R injury agents.
View details for DOI 10.1016/j.ejmech.2019.111729
View details for PubMedID 31655431
Scale-Up Synthesis and Identification of GLYX-13, a NMDAR Glycine-Site Partial Agonist for the Treatment of Major Depressive Disorder.
Molecules (Basel, Switzerland)
2018; 23 (5)
GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography-free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique.
View details for DOI 10.3390/molecules23050996
View details for PubMedID 29695090
View details for PubMedCentralID PMC6102568
Discovery of N-(Naphtho[1,2-b]Furan-5-Yl) Benzenesulfonamides as Novel Selective Inhibitors of Triple-Negative Breast Cancer (TNBC).
Molecules (Basel, Switzerland)
2018; 23 (3)
Any type of breast cancer not expressing genes of the estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER2) is referred to as triple-negative breast cancer (TNBC). Accordingly, TNBCs do not respond to hormonal therapies or medicines targeting the ER, PR, or HER2. Systemic chemotherapy is therefore the only treatment option available today and prognoses remain poor. We report the discovery and characterization of N-(naphtho[1,2-b]furan-5-yl)benzenesulfonamides as selective inhibitors of TNBCs. These inhibitors were identified by virtual screening and inhibited different TNBC cell lines with IC50 values of 2-3 μM. The compounds did not inhibit normal (i.e. MCF-7 and MCF-10A) cells in vitro, indicating their selectivity against TNBC cells. Considering the selectivity of these inhibitors for TNBC, these compounds and analogs can serve as a promising starting point for further research on effective TNBC inhibitors.
View details for DOI 10.3390/molecules23030678
View details for PubMedID 29547591
View details for PubMedCentralID PMC6017705