Medicine in Drug Discovery最新文献

Steroidal sulfatase (STS) is a group of arylsulfatase C enzymes that are involved in the metabolism of steroids. The increase in the circulation of the steroidogenic hormone Estradiol (E2) is responsible for causing breast cancer. Therefore, inhibitors of STS are proved to be an attractive target in the development of lead molecules against breast malignancy. In this work, Quantitative Structural Activity Relationship (QSAR) studies were performed on a dataset of 72 molecules of tricyclic coumarin analogs using random selection in QSARINS software and the statistical technique Genetic Algorithm coupled Multiple Linear Regression (MLR) was employed with the best model prediction R² = 0.86 and Q²_loo = 0.7913. The inclusion of descriptors Mor15m and Mor18v has developed a well-fitted and highly predictable model. Furthermore, the molecular docking and dynamics simulations helped us identify the binding interactions and estimate the stability of the complexes respectively. The binding analysis of the compounds into human sulfatase protein (PDB code: 1P49) resulted in prominent hydrophobic interactions with Arg98, Val486, Phe488, Gly100, Val101, and Lys368. The top-scoring compound 9o and compound 41 were studied for stability analysis in comparison with the standard Irosustat and the RMSD was found to be 5.4 Å. Based on our findings, we report the inclusion of the necessary structural features of coumarin derivatives leads to the development of potent candidates for further development.

Mucus is a viscoelastic hydrogel that lubricates and protects mucosal tissues such as the eyes, lung, gastrointestinal tract, and vagina. Nanoparticle-based drug delivery systems (DDSs) can be easily trapped in the mucus network by steric obstruction and/or binding interactions and then are efficiently cleared away with rapid mucus turnover, thereby limiting mucosal drug delivery efficacy. Modulating the physicochemical properties of nanoparticles (NPs), including size, surface hydrophilicity and charge, shape, and rigidity, is an effective method to overcome the mucus barrier. This review first describes the protective barrier properties of mucus and how mucus affects the fate of NPs. It then reviews the techniques for evaluating particle movement in mucus, including macroscopic diffusivity and microcosmic diffusion mechanisms. The state-of-the-art strategies exploited by researchers to overcome the mucus barrier by using NPs are discussed. Finally, the dilemma and solutions of balancing both mucus penetration and cellular uptake barriers are discussed.

Aims

Non-healing wounds are a major complication for the 27 million individuals in the United States with diagnosed diabetes. This study investigated the efficacy of a novel formulation to treat diabetic foot ulcers by targeting an underlying pathophysiology of diabetes.

Main methods

The proprietary GMP formulations utilized increasing dosages of naltrexone (NTX) to block the inhibitory peptide Opioid Growth Factor (OGF) from binding to the OGF receptor (OGFr). Efficacy of topical application was studied using male Sprague-Dawley rats with uncontrolled (T1D) or insulin-controlled (T1D-INS) diabetes. Wound closure time, tensile strength of healed skin, and angiogenesis were endpoints. Serum drug dispersion was assessed.

Key findings

Residual wound areas were significantly reduced within 2 days of surgery in T1D rats receiving either 0.5% or 1% NTX. By day 10, NTX-treated wounds were 5-fold smaller than those measured on T1D rats receiving vehicle. Tensile strength measurements and morphology studies revealed that NTX treatment of cutaneous wounds on T1D or T1D-INS rats accelerated epithelialization, accelerated angiogenesis, and increased the integrity of healed skin. Topical application of NTX resulted in no visible toxicity, and the NTX was not detected in serum.

Significance

Proprietary GMP formulations up to 1% NTX were found to be effective and safe for topical treatment of full-thickness cutaneous wounds in diabetic rats. The mechanism of action involves blockade of the OGF-OGFr axis, a pathway known to become dysregulated with diabetes. These data warrant proof-of-concept human clinical trials for treatment of diabetic foot ulcers.

ATP-adenosine signal axis plays an import role in tumor immune regulation. ATP released by tumor cells can promote antitumor immunity, and adenosine can suppress the immune response. CD39, also known as Nucleoside triphosphate diphosphohydrolase-1 (NTPDase1), can hydrolyze ATP into ADP and AMP, then transfer AMP to immunosuppressive adenosine. High expression of CD39 in tumor microenvironment (TME) disrupted the balance of pro-inflammation and anti-inflammation, attributed by ATP-adenosine metabolism. In order to evaluate the potency of targeting CD39 as a novel anti-tumor therapy, we generated a fully humanized anti-CD39 mAb, EMB04. In vitro and in vivo characterization of EMB04 demonstrated that EMB04 can efficiently block the ATPase activity of membrane-associated and soluble CD39 protein. EMB04 also suppressed tumor growth in the xenograft model of SCID mice. In summary, EMB04 is a potent highly efficient inhibitor of CD39 ATPase activity that may contribute to future immunotherapy for cancer.

Coronavirus disease-2019 has been one of the most challenging global epidemics of modern times with a large number of casualties combined with economic hardships across the world. Considering that there is still no definitive cure for the recent viral crisis, this article provides a review of nanomaterials with antiviral activity, with an emphasis on graphene and its derivatives, including graphene oxide, reduced graphene oxide and graphene quantum dots. The possible interactions between surfaces of such nanostructured materials with coronaviruses are discussed. The antiviral mechanisms of graphene materials can be related to events such as the inactivation of virus and/or the host cell receptor, electrostatic trapping and physico-chemical destruction of viral species. These effects can be enhanced by functionalization and/or decoration of carbons with species that enhances graphene-virus interactions. The low-cost and large-scale preparation of graphene materials with enhanced antiviral performances is an interesting research direction to be explored.

Adjuvants are essential components of vaccines that have been particularly effective at promoting protective humoral immunity to infectious diseases and preventing mortality and morbidity. There are many different types of adjuvants with different modes of action. A better understanding of their potential adjuvanticity could provide guidance for the development of novel adjuvants for cancer immunotherapy. In this article, we review the importance of adjuvants in vaccine development, their mechanisms of action and adjuvant-induced autoimmunity and discuss some strategies for driving the development of new vaccine adjuvants.

Recently, the strategy of using positively charged nanoparticles as new vaccine delivery systems has been widely investigated for enhancing the anti-infectious disease immune responses and has been found to efficiently improve the immune response through the targeting and activation of antigen-presenting cells. Acanthopanax senticosus polysaccharide (ASPS) is extracted from Acanthopanax senticosus and functions as an effective immunostimulatory drug. The present work encapsulated the ASPS immunopotentiator to the calcium carbonate (CaCO₃) microspheres, and adopted polyethylenimine, a cationic polymer, for coating the microspheres, finally developing the novel nanoparticle (NP) delivery system with positive charge (CaCO₃–ASPS–PEI). As a result, our constructed CaCO₃–ASPS–PEI remarkably up-regulated CD86 and MHCII and activated macrophages, while increasing TNF-α and IL-1β production via macrophages. Moreover, the mice immunized with porcine parvovirus (PPV) antigen adsorbed onto CaCO₃–ASPS–PEI nanoparticles had a significant enhancement in cytokine production, the PPV-specific IgG immune response, and the hybrid Th1/Th2 immune response (dominated by Th1), relative to the remaining groups. Based on the above results, our constructed CaCO₃–ASPS–PEI NPs with positive charge may be used as the efficient adjuvant vaccine delivery system for inducing the long-time potent immune responses.

Sleep-wakefulness is disrupted in most neurological and psychiatric disorders. Although clinical data implicate orexin (hypocretin), a crucial sleep/wake regulatory neuropeptide, in such disorders, limited sample volumes effectively prevent quantification of cerebrospinal fluid (CSF) levels of orexin A in mouse models of brain disorders. Current enzyme- and radio-immunoassays for orexin A generally require 50–100 µL CSF, whereas typical CSF sample volumes from mice are ~5–10 µL/mouse. We therefore aimed to develop and validate a liquid chromatography (LC) targeted mass spectrometry (MS) method for the absolute quantification of orexin A in the CSF of individual mice. LC coupled to tandem MS (LC-MS/MS) and a triple quadrupole (QQQ) mass spectrometer were used to develop a LC electrospray ionization multiple-reaction monitoring (LC-ESI-MRM) method. CSF orexin A levels of C57BL/6JARC mice were quantified using this method at the predicted peak and trough of diurnal orexin A release and following sleep deprivation. The LC-ESI-MRM assay was robust and sensitive, with an intra-assay variation <9% CV, inter-assay variation of 10% CV and limit of quantitation of 1.65 fmoles. CSF orexin A concentrations in C57/Bl6JARC mice were higher in the late active period (2.5 ± 0.5 fmoles/µL) versus the late inactive period (1.2 ± 0.5 fmoles/µL, p < 0.001). Sleep deprivation significantly dysregulated diurnal rhythm, up-regulating orexin A acutely, followed by down-regulation 16 hours after sleep deprivation. We anticipate this validated LC-ESI-MRM assay for the absolute quantification of orexin A in the CSF of individual mice will enhance research using relevant rodent models of sleep or arousal-related brain disorders.

Determination of orexin-A level in the cerebrospinal fluid is a central diagnostic tool in narcolepsy diagnostics. There is also much interest in determining the orexin levels in other disorders of sleep and wakefulness and even in completely different perspectives. Radioimmunoassay on lumbar puncture samples is the standard method for the quantitation. However, there are problems related to this method and thus recently have even mass spectrometry-based identification methods been developed for orexin-A. Unfortunately, even these have not been quite able to deliver what was expected. In this short review, I review and assess the use and the performance of each method and present the open questions and the hypotheses to answer these.