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1.
J Med Chem ; 67(1): 433-449, 2024 01 11.
Article in English | MEDLINE | ID: mdl-38112492

ABSTRACT

Proprotein convertase subtilisin/kexin type-9 (PCSK9), a secreted protein that is synthesized and spontaneously cleaved in the endoplasmic reticulum, has become a hot lipid-lowering target chased by pharmaceutical companies in recent years. Autophagosome-tethering compounds (ATTECs) represent a new strategy to degrade targeted biomolecules. Here, we designed and synthesized PCSK9·ATTECs that are capable of lowering PCSK9 levels via autophagy in vivo, providing the first report of the degradation of a secreted protein by ATTECs. OY3, one of the PCSK9·ATTECs synthesized, shows greater potency to reduce plasma low-density lipoprotein cholesterol (LDL-C) levels and improve atherosclerosis symptoms than treatment with the same dose of simvastatin. OY3 also significantly reduces the high expression of PCSK9 caused by simvastatin administration in atherosclerosis model mice and subsequently increases the level of low-density lipoprotein receptor, promoting simvastatin to clear plasma LDL-C and alleviate atherosclerosis symptoms. Thus, we developed a new candidate compound to treat atherosclerosis that could also promote statin therapy.


Subject(s)
Atherosclerosis , Proprotein Convertase 9 , Mice , Animals , Proprotein Convertase 9/metabolism , Cholesterol, LDL/metabolism , Cholesterol, LDL/therapeutic use , Simvastatin/pharmacology , Simvastatin/therapeutic use , Receptors, LDL/metabolism , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Autophagy
2.
Bioorg Med Chem Lett ; 59: 128544, 2022 03 01.
Article in English | MEDLINE | ID: mdl-35031453

ABSTRACT

Nitric oxide (NO) is an essential cellular messenger molecule involved in various physiological and pathological processes. Thus, monitoring the dynamic presence of endogenous NO in living cells is of great significance. In this paper, we developed an activatable fluorescent nanoprobe BOD-NH-NP for endogenous NO detection. In the probe BOD-NH-NP, the fast responding reaction site towards NO, incorporating a BODIPY fluorescent dye with good optical features, enables the probe to be applied for the detection of endogenous NO via the eNOS enzymatic pathway in living cells and screening nitric oxide synthases (NOSs) inhibitors and agonists.


Subject(s)
Fluorescent Dyes/chemistry , Nitric Oxide Synthase Type III/metabolism , Nitric Oxide/analysis , Animals , Cell Line , Molecular Structure , Nitric Oxide/metabolism , Optical Imaging , Rats
3.
Anal Chem ; 93(48): 16158-16165, 2021 12 07.
Article in English | MEDLINE | ID: mdl-34813273

ABSTRACT

Real-time in vivo optical imaging of kidney function is important for the diagnosis of renal diseases, such as acute kidney injury (AKI) and chronic kidney disease (CKD), with high morbidity and mortality worldwide. However, the reported optical imaging agents still have limitations for identifying AKI or CKD in the early stage due to their low sensitivity, poor tissue penetration, and significant background interference. Herein, an N-acetyl-ß-d-glucosaminidase (NAG)-activatable second near-infrared (NIR-II) fluorescent nanoprobe (BOD-II-NAG-NP) is developed for monitoring the progression of drug-induced AKI and in vivo imaging of diabetes-caused CKD. NAG, as a biomarker of renal diseases, is able to specifically activate BOD-II-NAG-NP to release NIR-II fluorescence signals, enabling in vivo imaging of kidney dysfunctions in living mice. Importantly, such an active imaging mechanism allows BOD-II-NAG-NP to noninvasively detect the onset of drug-induced AKI at least 32 h earlier than the most existing assays, which indicates that BOD-II-NAG-NP has the potential to be an optical imaging agent for the early diagnosis of AKI. Moreover, NIR-II fluorescence produced by BOD-II-NAG-NP could deeply penetrate into the relatively thick layers of fat in diabetic nephropathy mice and provide in vivo imaging with high resolution, indicating that BOD-II-NAG-NP has clinical potential for precision diagnosis of CKD.


Subject(s)
Acute Kidney Injury , Diabetes Mellitus , Pharmaceutical Preparations , Renal Insufficiency, Chronic , Acetylglucosaminidase , Acute Kidney Injury/chemically induced , Acute Kidney Injury/diagnostic imaging , Animals , Biomarkers , Mice , Renal Insufficiency, Chronic/chemically induced , Renal Insufficiency, Chronic/diagnostic imaging
4.
Anal Chem ; 92(18): 12613-12621, 2020 09 15.
Article in English | MEDLINE | ID: mdl-32786453

ABSTRACT

Senescence-associated diseases have severely diminished the quality of life and health of patients. However, a sensitive assay of these diseases remains limited due to a lack of straightforward methods. Considering that senescence-associated ß-galactosidase (SA-ß-Gal) is overexpressed in senescent cells, the detection of SA-ß-Gal in senescent cells and tissues might be a feasible strategy for the early diagnosis of SA diseases. In this study, a ß-galactosidase-activatable nanoprobe BOD-L-ßGal-NPs was developed for the imaging of senescent cells and vasculature in atherosclerotic mice via real-time monitoring of ß-Gal. BOD-L-ßGal-NPs was fabricated by encapsulating a newly designed NIR ratiometric probe BOD-L-ßGal within a poly(lactic-co-glycolic) acid (PLGA) core. Nanoprobe BOD-L-ßGal-NPs showed good accumulation in arteries, thus successfully visualizing senescent cells and vasculature in atherosclerotic mice by tail vein injection. Our findings indicated that nanoprobe BOD-L-ßGal-NPs holds great potential for the early diagnosis and therapy of atherosclerosis and other aging-associated diseases.


Subject(s)
Atherosclerosis/diagnosis , Boron/chemistry , Fluorescent Dyes/chemistry , Nanoparticles/chemistry , Porphobilinogen/analogs & derivatives , beta-Galactosidase/analysis , Animals , Atherosclerosis/metabolism , Boron/metabolism , Cellular Senescence , Fluorescent Dyes/metabolism , Male , Mice , Mice, Inbred C57BL , Molecular Structure , Nanoparticles/metabolism , Porphobilinogen/chemistry , Porphobilinogen/metabolism , Rats , Rats, Sprague-Dawley , beta-Galactosidase/genetics , beta-Galactosidase/metabolism
5.
Chem Commun (Camb) ; 56(18): 2731-2734, 2020 Mar 04.
Article in English | MEDLINE | ID: mdl-32022000

ABSTRACT

We herein develop two ß-galactosidase (ß-Gal) activatable NIR fluorescent probes for visualizing ovarian cancers. Particularly, probe BOD-M-ßGal produced NIR-II emission light at 900-1300 nm upon ß-Gal activation. By using our activatable and target specific NIR-II probe for deep-tissue imaging of ß-Gal overexpressed ovarian cancer cells, rapid and accurate imaging of ovarian tumors in nude mice was achieved.


Subject(s)
Fluorescent Dyes/chemistry , Optical Imaging , Ovarian Neoplasms/diagnostic imaging , beta-Galactosidase/chemistry , Animals , Cell Line, Tumor , Enzyme Activation , Female , Fluorescent Dyes/metabolism , Human Umbilical Vein Endothelial Cells/chemistry , Humans , Infrared Rays , Mice , Mice, Nude , Molecular Structure , Neoplasms, Experimental/diagnostic imaging , Neoplasms, Experimental/metabolism , Ovarian Neoplasms/metabolism , beta-Galactosidase/metabolism
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