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Increasing antibiotic resistance and beneficial effects of host microbiota has motivated the search for anti-infective agents that attenuate bacterial virulence rather than growth. For example, we discovered that specific flavonoids such as baicalein and quercetin from traditional medicinal plant extracts could attenuate Salmonella enterica serovar Typhimurium type III protein secretion and invasion of host cells. Here, we show epigallocatechin-3-gallate from green tea extracts also inhibits the activity of S. Typhimurium type III protein effectors and significantly reduces bacterial invasion into host cells. These results reveal additional dietary plant metabolites that can attenuate bacterial virulence and infection of host cells. [ABSTRACT FROM AUTHOR]

Traditional Chinese Medicines (TCMs) have been historically used to treat bacterial infections. However, the molecules responsible for these anti-infective properties and their potential mechanisms of action have remained elusive. Using a high-throughput assay for type III protein secretion in Salmonella enterica serovar Typhimurium, we discovered that several TCMs can attenuate this key virulence pathway without affecting bacterial growth. Among the active TCMs, we discovered that baicalein, a specific flavonoid from Scutellaria baicalensis, targets S. Typhimurium pathogenicity island-1 (SPI-l) type III secretion system (T3SS) effectors and translocases to inhibit bacterial invasion of epithelial cells. Structurally related flavonoids present in other TCMs, such as quercetin, also inactivated the SPI-1 T3SS and attenuated S. Typhimurium invasion. Our results demonstrate that specific plant metabolites from TCMs can directly interfere with key bacterial virulence pathways and reveal a previously unappreciated mechanism of action for anti-infective medicinal plants. [ABSTRACT FROM AUTHOR]

Protein–protein interactions lie at the heart of cellular signaling pathways and the deregulation of which has frequently led to diseases. In contrast to inhibitors that bind to distinctive enzyme active sites, molecules targeting protein surface topologies have been underexploited in drug development. The challenges in developing protein surface antagonists or agonists originate from the relatively large and flat surface areas that lack well-defined cavities required for sufficient binding affinity. In the past decade, our understanding of protein recognition has served as solid basis for the design of synthetic mimetics to modulate these protein–protein interactions. Herein, we summarize recent successes in the development of synthetic α-helix mimetics, proteomimetics, and biologics with the therapeutic potentials of inhibiting tumorgenesis or cancer-related viral infections. [Copyright &y& Elsevier]

Abstract: We report the mode of action of a proteomimetic compound that binds to the exterior surface of gp120 and blocks HIV-1 entry into cells. Using a one cycle time-of-addition study and antibody competition binding studies, we have determined that the compound blocks HIV-1 entry through modulation of key protein–protein interactions mediated by gp120. The compound exhibits anti-HIV-1 replication activities against several pseudotype viruses derived from primary isolates and the resistant strains isolated from existing drug candidates with equal potency. Together, these data provide evidence that the proteomimetic compound represents a novel class of HIV-1 viral entry inhibitor that functions through protein surface recognition in analogy to an antibody. [Copyright &y& Elsevier]

Cation-π interactions have been proposed to be important contributors to protein structure and function. In particular, these interactions have been suggested to provide significant stability at the solventexposed surface of a protein. We have investigated the magnitude of cation-π interactions between phenylalanine (Phe) and lysine (Lys), ornithine (Orn), and diaminobutanoic acid (Dab) in the context of an α-helix and have found that only the Phe···Orn interaction provides significant stability to the helix, stabilizing it by -0.4 kcal/mol. This interaction energy is in the same range as a salt bridge in an α-helix, and equivalent to the recently reported Trp···Arg interaction in an α-helix, despite the fact that Trp···guanidinium interactions have been proposed to be stronger than Phe···ammonium interactions. These results indicate that even the simplest cation-π interaction can provide significant stability to protein structure and demonstrate the subtle factors that can influence the observed interaction energies in designed systems. [ABSTRACT FROM AUTHOR]

Abstract: A potential anti-HIV and HCV drug candidate is highly desirable as coinfection has become a worldwide public health challenge. A potent compound based on a tetrabutoxy-calix[4]arene scaffold that possesses dual inhibition for both HIV and HCV is described. Structural activity relationship studies demonstrate the effects of lower-rim alkylation in maintaining cone conformation and upper-rim interacting head groups on the calix[4]arene play key roles for its potent dual antiviral activities. [Copyright &y& Elsevier]

Abstract: A set of macrocycles was generated by solid phase synthesis of linear trimers of 5-aminoacyl-3-aminomethyl-benzoates followed by resin cleavage and solution phase macrocyclization. These scaffolds can serve as useful building blocks for molecular recognition studies, especially where differentially functionalized molecular platforms spanning large surface areas are required. [Copyright &y& Elsevier]

Machine learning is a well-known approach for virtual screening. Recently, deep learning, a machine learning algorithm in artificial neural networks, has been applied to the advancement of precision medicine and drug discovery. In this study, we performed comparative studies between deep neural networks (DNN) and other ligand-based virtual screening (LBVS) methods to demonstrate that DNN and random forest (RF) were superior in hit prediction efficiency. By using DNN, several triple-negative breast cancer (TNBC) inhibitors were identified as potent hits from a screening of an in-house database of 165,000 compounds. In broadening the application of this method, we harnessed the predictive properties of trained model in the discovery of G protein-coupled receptor (GPCR) agonist, by which computational structure-based design of molecules could be greatly hindered by lack of structural information. Notably, a potent (~ 500 nM) mu-opioid receptor (MOR) agonist was identified as a hit from a small-size training set of 63 compounds. Our results show that DNN could be an efficient module in hit prediction and provide experimental evidence that machine learning could identify potent hits in silico from a limited training set. [ABSTRACT FROM AUTHOR]

The article discusses the use of a carboxypeptidase G2 (CPG2)-based reporter system to detect the type III protein secretion from Gram-negative bacterial pathogens. Researchers synthesize a glutamate (Glu)-modified derivative of 2-dicyanomethylene-3-cyano-2,5-dihydrofuran (CyFur) to be used as a fluorogenic substrate for CPG2 and explore the sensitivity of the CPG:Gu-CyFur reporter system. It is noted that this system can monitor protein expression and secretion with sensitivity.

We have discovered a novel series of quinazoline-based CXCR4 antagonists. Of these, compound 19 mobilized CXCR4+ cell types, including hematopoietic stem cells and endothelial progenitor cells, more efficiently than the marketed 1 (AMD3100) with subcutaneous administration at the same dose (6 mg/kg) in mice. This series of compounds thus provides a set of valuable tools to study diseases mediated by the CXCR4/SDF-1 axis, including myocardial infarction, ischemic stroke, and cancer metastasis. More importantly, treatment with compound 19 significantly lowered levels of blood urea nitrogen and serum creatinine in rats with renal ischemia-reperfusion injury, providing evidence for its therapeutic potential in preventing ischemic acute kidney injury. CXCR4 antagonists such as 19 might also be useful to increase circulating levels of adult stem cells, thereby exerting beneficial effects on damaged and/or inflamed tissues in diseases that currently are not treated by standard approaches. [ABSTRACT FROM AUTHOR]

Motivatedby the pivotal role of CXCR4 as an HIV entry co-receptor,we herein report a de novo hit-to-lead effort on the identificationof subnanomolar purine-based CXCR4 antagonists against HIV-1 infection.Compound 24, with an EC50of 0.5 nM againstHIV-1 entry into host cells and an IC50of 16.4 nM forinhibition of radioligand stromal-derived factor-1α (SDF-1α)binding to CXCR4, was also found to be highly selective against closelyrelated chemokine receptors. We rationalized that compound 24complementarily interacted with the critical CXCR4 residues thatare essential for binding to HIV-1 gp120 V3 loop and subsequent viralentry. Compound 24showed a 130-fold increase in anti-HIVactivity compared to that of the marketed CXCR4 antagonist, AMD3100(Plerixafor), whereas both compounds exhibited similar potency inmobilization of CXCR4+/CD34+stem cells at ahigh dose. Our study offers insight into the design of anti-HIV therapeuticsdevoid of major interference with SDF-1α function. [ABSTRACT FROM AUTHOR]

We report the design, synthesis and evaluation of a class of phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates and show that conjugate 16b elicits immune cell infiltration and remodels the "cold" hepatic tumor microenvironment to the inflamed "hot" tumor. Structure-property relationship study via linker modifications and subsequent pharmacokinetics profiling were carried out to improve the solubility and stability of the conjugates in vivo. In a spontaneous hepatocellular carcinoma mouse model, we showed that conjugate 16b exhibited better antitumor efficacy than sorafenib. In particular, significant increase of CD8+ T cell infiltration and granzyme B level was observed, providing insights in sensitizing tumors from intrinsic immune suppressive microenvironment. Evaluation of tumor inflammation-related mRNA expression profile revealed that conjugate 16b, through inductions of key gene expressions including STAT1, CXCL9, CCL5, and PD-L1, rejuvenated tumor microenvironment with enhancement in T cell-, macrophage-, NK cell-, chemokines and cytokines'- functions. Our study establishes that an apoptosis-targeting theranostic enables enrichment of multifaceted immune cells into the tumor mass, which provides potential therapeutic strategies in the combination with immune checkpoint blockade treatment. [Display omitted] • Designing phosphatidylserine-targeting zinc (II) dipicolylamine drug conjugates. • Reducing hepatic tumor burden and increasing immune cells infiltration. • Remodeling of hepatic tumor microenvironment to inflamed "hot" tumor. [ABSTRACT FROM AUTHOR]