The concept of drug-likeness has been established in the field of drug discovery. Pesticide discovery is also a complicated and rigorous filtering process compared with drug discovery. This study involved investigation of the constitutive properties of 788 marketed pesticides, including 341 herbicides, 182 fungicides, and 265 insecticides. In a comparison of the constitutive properties of different kinds of pesticides and of pesticides from different periods of registration, ClogP, the number of H-bond donors (HBD), and the number of aromatic bonds (ARB) were identified as the most important factors that distinguish herbicides, fungicides, and insecticides. In addition, the reduction in pesticide toxicity with revolution time was found to have some relationship with an increase in values of the six constitutive properties. Finally, we established some rules for pesticide-likeness, including molecular weight≤435 Da, ClogP≤6, number of H-bond acceptors (HBA)≤6, HBD≤2, number of rotatable bonds (ROB)≤9, and ARB≤17. The constitutive property-related novel findings in this study will promote the structure-based optimization of pesticide candidates.

Selenocysteine (Sec), encoded as the 21st amino acid, is the predominant chemical form of selenium that is closely related to various human diseases. Thus, it is of high importance to identify novel probes for sensitive and selective recognition of Sec and Sec-containing proteins. Although a few probes have been reported to detect artificially introduced selenols in cells or tissues, none of them has been shown to be sensitive enough to detect endogenous selenols. We report the characterization and application of a new fluorogenic molecular probe for the detection of intracellular selenols. This probe exhibits near-zero background fluorescence but produces remarkable fluorescence enhancement upon reacting with selenols in a fast chemical reaction. It is highly specific and sensitive for intracellular selenium-containing molecules such as Sec and selenoproteins. When combined with flow cytometry, this probe is able to detect endogenous selenols in various human cancer cells. It is also able to image endogenous selenol-containing molecules in zebrafish under a fluorescence microscope. These results demonstrate that this molecular probe can function as a useful molecular tool for intracellular selenol sensing, which is valuable in the clinical diagnosis for human diseases associated with Sec-deficiency or overdose.

Human neutrophil elastase (HNE) has been identified as a potential therapeutic target for the discovery of anti-inflammatory drugs for decades. However, little progress has been made on assays measuring the activity of HNE, especially on synthetic substrates which play essential role in determination of HNE activity. Herein, a small-molecule compound, 2,2,3,3,3-pentafluoro-N-(2-oxo-4-(trifluoromethyl)-2H-chromen-7-yl)-propanamide (compound 4), has been successfully designed as the first ever non-peptide-based fluorogenic substrate for HNE. A "turn-on" fluorometric assay based on 4 has been successfully developed for rapid determination of HNE activity and the inhibitory kinetic study. Most importantly, the probe 4 shows highly specific response for HNE among seven tested hydrolases or proteins and can be directly used to detect the elevated HNE activity in the serum of chronic obstructive pulmonary disease (COPD) patients compared to that of healthy controls. This specific and cost-effective probe will facilitate future high-throughput discovery of HNE inhibitors and clinical diagnosis of elastase-related diseases.

No abstract

There is an increasing demand for effective noninvasive diagnosis against common pulmonary diseases, which are rising sharply due to the serious air pollution. Human neutrophil elastase (HNE), a typical protease highly involved in pulmonary inflammatory diseases and lung cancer, is a potential predictor for disease progression. Currently, few of the HNE-targeting probes are applicable in vivo due to the limitation in sensitivity and biocompatibility. Herein, we reported the achievement of in vitro detection and in vivo imaging of HNE by incorporating the HNE-specific peptide substrate, quantum dots (QDs), and organic dyes into the fluorescence resonance energy transfer (FRET) system. The refined nanoprobe, termed QDP, could specifically measure the HNE with excellent sensitivity of 7.15 pM in aqueous solution and successfully image the endogenous and exogenous HNE in living cells. In addition, this nanoprobe enabled HNE imaging in mouse models of lung cancer and acute lung injury, and the HNE activity at high temporal and spatial resolution was continuously monitored. Most importantly, QDP successfully discriminated the serums of patients with lung diseases from those of the healthy controls based on the HNE activity determination. Overall, this study demonstrates the advantages of a FRET-system-based nanoprobe in imaging performance and provides an applicable tool for in vivo HNE detection and pulmonary disease diagnosis.

Our results suggest that the specificity and image quality of [(99m)Tc]cFLFLF are superior to those of the [(99m)Tc]MDP and [(18)F]DFG imaging probes currently used for early diagnosis of AO. Furthermore, [(99m)Tc]cFLFLF was able to effectively evaluate the therapeutic response to antibiotic treatment of AO. Our data suggest that [(99m)Tc]cFLFLF is a promising imaging agent for detection of infectious diseases.

Tumor periphery and lymph nodes of tumorinduced lymphangiogenesis often abundantly express VEGFR-3. In our previous study, we identified a 5-amino acid peptide named TMVP1, which binds specifically to VEGFR-3. The objective of this study was to develop a novel 68 Ga-labeled TMVP1 for VEGFR-3 PET imaging and to investigate its safety, biodistribution, and tumor-localizing efficacy in xenograft tumor models and a small cohort of patients with recurrent ovarian and cervical cancer.Experimental Design: The DOTA-conjugated TMVP1 peptide was labeled with radionuclide 68 Ga. SPR and saturation binding assays were used for the receptor-binding studies. Gynecologic xenograft tumors were employed for small-animal PET imaging and biodistribution of 68 Ga-DOTA-TMVP1 in vivo. In the clinical study, 5 healthy volunteers and 8 patients with gynecologic cancer underwent whole-body PET/CT after being injected with 68 Ga-DOTA-TMVP1.Results: DOTA-TMVP1 was successfully labeled with 68 Ga. LECs showed higher binding capacity with 68 Ga-DOTA-TMVP1 than LEC(shVEGFR-3) and human umbilical vein endothelial cells. In mice with subcutaneous C33-A and SKOV-3 xenografts, the tracer was rapidly eliminated through the kidney to the bladder, and the small-animal PET/CT helped to clearly visualize the tumors. In patients with recurrent ovarian cancer and cervical cancer, tracer accumulation well above the background level was demonstrated in most identified sites of disease; especially with recurrent endodermal sinus tumors, the diagnostic value of 68 Ga-DOTA-TMVP1 was comparable with that of 18 F-FDG PET/CT.Conclusions: 68 Ga-DOTA-TMVP1 is a potential PET tracer for imaging VEGFR-3 with favorable pharmacokinetics.

Loading chemotherapeutic drugs into MGNs can increase antitumor potency, reduce normal cell damage and decrease drug resistance, thus representing a promising approach for advanced prostate cancer treatment.