Exploring the 1,3-benzoxazine chemotype for cannabinoid receptor 2 as a promising anti-cancer therapeutic.

The discovery of selective agonists of cannabinoid receptor 2 (CB) is strongly pursued to successfully tuning endocannabinoid signaling for therapeutic purposes. However, the design of selective CB agonists is still challenging because of the high homology with the cannabinoid receptor 1 (CB) and for the yet unclear molecular basis of the agonist/antagonist switch. Here, the 1,3-benzoxazine scaffold is presented as a versatile chemotype for the design of CB agonists from which 25 derivatives were synthesized.

Recent Advances on Type-2 Cannabinoid (CB) Receptor Agonists and their Therapeutic Potential.

In the last decade, selective modulators of type-2 cannabinoid receptor (CB) have become a major focus to target endocannabinoid signaling in humans. Indeed, heterogeneously expressed within our body, CB actively regulates several physio-pathological processes, thus representing a promising target for developing specific and safe therapeutic drugs. If CB modulation has been extensively studied since the very beginning for the treatment of pain and inflammation, the more recent involvement of this receptor in other pathological conditions has further strengthened the pursuit of novel CB agonists in the last five years.

Nitazoxanide inhibits paramyxovirus replication by targeting the Fusion protein folding: role of glycoprotein-specific thiol oxidoreductase ERp57.

Paramyxoviridae, a large family of enveloped viruses harboring a nonsegmented negative-sense RNA genome, include important human pathogens as measles, mumps, respiratory syncytial virus (RSV), parainfluenza viruses, and henipaviruses, which cause some of the deadliest emerging zoonoses. There is no effective antiviral chemotherapy for most of these pathogens. Paramyxoviruses evolved a sophisticated membrane-fusion machine consisting of receptor-binding proteins and the fusion F-protein, critical for virus infectivity.

Design, Synthesis, and Biological Evaluation of Tetrahydro-β-carboline Derivatives as Selective Sub-Nanomolar Gelatinase Inhibitors.

Targeting matrix metalloproteinases (MMPs) is a pursued strategy for treating several pathological conditions, such as multiple sclerosis and cancer. Herein, a series of novel tetrahydro-β-carboline derivatives with outstanding inhibitory activity toward MMPs are present. In particular, compounds 9 f, 9 g, 9 h and 9 i show sub-nanomolar IC values.

Interactions between integrase inhibitors and human arginase 1.

The neuro-pathogenic mechanism(s) underlying HIV-associated neurocognitive disorders are mostly unknown. HIV-infected macrophages and microglial cells play a crucial role and the metabolic fate of l-arginine may be highly relevant to microglia activation. In this context, arginase (ARG), which uses l-arginine as substrate, can be on the same time a target and source of oxidative stress and inflammation.

Antiretrovirals inhibit arginase in human microglia.

Preliminary evidence in an animal model, that is, primary cultures of rat microglia cells, suggested that some antiretroviral drugs (ARVs), namely darunavir, atazanavir, efavirenz, and nevirapine, increase NO production through a mechanism involving the inhibition of arginase (ARG) activity. This study was conceived to investigate the effects of ARVs on ARG activity in a human experimental model. We compared CHME-5 human microglial immortalized cells under basal conditions with cells exposed to either IL-4, a mix of inflammatory cytokines, or both stimuli given together.

In silico scaffold evaluation and solid phase approach to identify new gelatinase inhibitors.

Among matrix metalloproteinases (MMPs), gelatinases MMP-2 (gelatinase A) and MMP-9 (gelatinase B) play a key role in a number of physiological processes such as tissue repair and fibrosis. Many evidences point out their involvement in a series of pathological events, such as arthritis, multiple sclerosis, cardiovascular diseases, inflammatory processes and tumor progression by degradation of the extracellular matrix. To date, the identification of non-specific MMP inhibitors has made difficult the selective targeting of gelatinases.

GPR55: Current knowledge and future perspectives of a purported "Type-3" cannabinoid receptor.

In the last decade, accumulated evidence highlighted that GPR55 might be activated by several classical cannabinoid ligands, making this orphan receptor the main candidate to be considered as the "third" cannabinoid receptor. The investigation of its pharmacology has often provided divergent and more intricate results that have complicated the understanding of the physiological role of GPR55. Nevertheless, the patent analysis regarding GPR55 outlines the fair interest of big pharmaceutical companies, especially in the first years of this decade.

Thiopyrophosphoantigens: solid-phase synthesis and in vitro characterization of a new class of Vgamma9 Vdelta2 T cells activators.

The Vgamma9 Vdelta2 T cells mediate rapid, innate-like immune responses to pathogens and are important in several key immunoregulatory pathways, including those involved in infections and tumor development. Vgamma9 Vdelta2 T cells respond to low molecular weight isoprenoid phosphoantigens; the prototypic stimulatory compound is isopentenylpyrophosphate (IPP), an alkylphosphate intermediate of mevalonate metabolism that elicits proliferative, cytotoxic, and cytokine secretion responses. We studied the replacement of the pyrophosphate moiety with the thiopyrophosphate bioisostere, synthesizing thioanalogues of IPP and 4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP, the most potent natural antigen known to date).

Structural bases for substrate and inhibitor recognition by matrix metalloproteinases.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases which are involved in the proteolytic processing of several components of the extracellular matrix. As a consequence, MMPs are implicated in several physiological and pathological processes, like skeletal growth and remodelling, wound healing, cancer, arthritis, and multiple sclerosis, raising a very widespread interest toward this class of enzymes as potential therapeutic targets. Here, structure-function relationships are discussed to highlight the role of different MMP domains on substrate/inhibitor recognition and processing and to attempt the formulation of advanced guidelines, based on natural substrates, for the design of inhibitors more efficient in vivo.

2-Arylpropionic CXC chemokine receptor 1 (CXCR1) ligands as novel noncompetitive CXCL8 inhibitors.

The CXC chemokine CXCL8/IL-8 plays a major role in the activation and recruitment of polymorphonuclear (PMN) cells at inflammatory sites. CXCL8 activates PMNs by binding the seven-transmembrane (7-TM) G-protein-coupled receptors CXC chemokine receptor 1 (CXCR1) and CXC chemokine receptor 2 (CXCR2). (R)-Ketoprofen (1) was previously reported to be a potent and specific noncompetitive inhibitor of CXCL8-induced human PMNs chemotaxis.