Novel orally bioavailable piperidine derivatives as extracellular arginase inhibitors developed by a ring expansion.

Arginase is a multifaced enzyme that plays an important role in health and disease being regarded as a therapeutic target for the treatment of various pathological states such as malignancies, asthma, and cardiovascular disease. The discovery of boronic acid-based arginase inhibitors in 1997 revolutionized attempts of medicinal chemistry focused on development of drugs targeting arginase. Unfortunately, these very polar compounds had limitations such as analysis and purification without chromophores, synthetically challenging space, and poor oral bioavailability.

OATD-02 Validates the Benefits of Pharmacological Inhibition of Arginase 1 and 2 in Cancer.

Background: Arginases play essential roles in metabolic pathways, determining the fitness of both immune and tumour cells. Along with the previously validated role of ARG1 in cancer, the particular significance of ARG2 as a therapeutic target has emerged as its levels correlate with malignant phenotype and poor prognosis. These observations unveil arginases, and specifically ARG2, as well-validated and promising therapeutic targets.

Discovery of , a First-in-Class Chitinase Inhibitor as Potential New Therapeutics for Idiopathic Pulmonary Fibrosis.

Chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) are the enzymatically active chitinases that have been implicated in the pathology of chronic lung diseases such as asthma and interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and sarcoidosis. The clinical and preclinical data suggest that pharmacological inhibition of CHIT1 might represent a novel therapeutic approach in IPF. Structural modification of an advanced lead molecule led to the identification of compound (, a highly active CHIT1 inhibitor with both an excellent PK profile in multiple species and selectivity against a panel of other off-targets.

Boronic acid-based arginase inhibitors in cancer immunotherapy.

Arginase is an enzyme that converts l-arginine to l-ornithine and urea in the urea cycle. There are two isoforms of arginase in mammals: ARG-1 and ARG-2. l-Arginine level changes occur in patients with various types of affliction.

Development of Dual Chitinase Inhibitors as Potential New Treatment for Respiratory System Diseases.

Acidic mammalian chitinase (AMCase) and chitotriosidase-1 (CHIT1) are two enzymatically active proteins produced by mammals capable of cleaving the glycosidic bond in chitin. Based on the clinical findings and animal model studies, involvement of chitinases has been suggested in several respiratory system diseases including asthma, COPD, and idiopathic pulmonary fibrosis. Exploration of structure-activity relationships within the series of 1-(3-amino-1-1,2,4-triazol-5-yl)-piperidin-4-amines, which was earlier identified as a scaffold of potent AMCase inhibitors, led us to discover highly active dual (i.

Small extracellular vesicles containing arginase-1 suppress T-cell responses and promote tumor growth in ovarian carcinoma.

Tumor-driven immune suppression is a major barrier to successful immunotherapy in ovarian carcinomas (OvCa). Among various mechanisms responsible for immune suppression, arginase-1 (ARG1)-carrying small extracellular vesicles (EVs) emerge as important contributors to tumor growth and tumor escape from the host immune system. Here, we report that small EVs found in the ascites and plasma of OvCa patients contain ARG1.

Discovery of selective, orally bioavailable inhibitor of mouse chitotriosidase.

This article describes our work towards the identification of a potent and selective inhibitor of mouse chitotriosidase (mCHIT1). A series of small molecule inhibitors of mCHIT1 and mAMCase have been developed from early lead compound 1. Examination of synthetized analogues led to discovery of several novel highly potent compounds.

Characteristics of Multifunctional, Eco-Friendly Lignin-Al₂O₃ Hybrid Fillers and Their Influence on the Properties of Composites for Abrasive Tools.

The main aim of the present study was the preparation and comprehensive characterization of innovative additives to abrasive materials based on functional, pro-ecological lignin-alumina hybrid fillers. The behavior of lignin, alumina and lignin-Al₂O₃ hybrids in a resin matrix was explained on the basis of their surface and application properties determined by inverse gas chromatography, the degree of adhesion/cohesion between components, thermomechanical and rheological properties. On the basis of the presented results, a hypothetical mechanism of interactions between lignin and Al₂O₃ as well as between lignin-Al₂O₃ hybrids and phenolic resins was proposed.

Correction: Turing Patterning Using Gene Circuits with Gas-Induced Degradation of Quorum Sensing Molecules.

[This corrects the article DOI: 10.1371/journal.pone.

Transcriptional regulation with CRISPR-Cas9: principles, advances, and applications.

CRISPR-Cas9 has recently emerged as a promising system for multiplexed genome editing as well as epigenome and transcriptome perturbation. Due to its specificity, ease of use and highly modular programmable nature, it has been widely adopted for a variety of applications such as genome editing, transcriptional inhibition and activation, genetic screening, DNA localization imaging, and many more. In this review, we will discuss non-editing applications of CRISPR-Cas9 for transcriptome perturbation, metabolic engineering, and synthetic biology.

Turing Patterning Using Gene Circuits with Gas-Induced Degradation of Quorum Sensing Molecules.

The Turing instability was proposed more than six decades ago as a mechanism leading to spatial patterning, but it has yet to be exploited in a synthetic biology setting. Here we characterize the Turing instability in a specific gene circuit that can be implemented in vitro or in populations of clonal cells producing short-range activator N-Acyl homoserine lactone (AHL) and long-range inhibitor hydrogen peroxide (H2O2) gas. Slowing the production rate of the AHL-degrading enzyme, AiiA, generates stable fixed states, limit cycle oscillations and Turing patterns.

Orthogonal Modular Gene Repression in Escherichia coli Using Engineered CRISPR/Cas9.

The progress in development of synthetic gene circuits has been hindered by the limited repertoire of available transcription factors. Recently, it has been greatly expanded using the CRISPR/Cas9 system. However, this system is limited by its imperfect DNA sequence specificity, leading to potential crosstalk with host genome or circuit components.

Pacemaker interactions induce reentrant wave dynamics in engineered cardiac culture.

Pacemaker interactions can lead to complex wave dynamics seen in certain types of cardiac arrhythmias. We use experimental and mathematical models of pacemakers in heterogeneous excitable media to investigate how pacemaker interactions can be a mechanism for wave break and reentrant wave dynamics. Embryonic chick ventricular cells are cultured in vitro so as to create a dominant central pacemaker site that entrains other pacemakers in the medium.

Scaling properties of conduction velocity in heterogeneous excitable media.

Waves of excitation through excitable media, such as cardiac tissue, can propagate as plane waves or break up to form reentrant spiral waves. In diseased hearts reentrant waves can be associated with fatal cardiac arrhythmias. In this paper we investigate the conditions that lead to wave break, reentry, and propagation failure in mathematical models of heterogeneous excitable media.