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.

The Anti-Inflammatory Effect of Acidic Mammalian Chitinase Inhibitor OAT-177 in DSS-Induced Mouse Model of Colitis.

Inflammatory bowel diseases (IBD) are chronic and relapsing gastrointestinal disorders, where a significant proportion of patients are unresponsive or lose response to traditional and currently used therapies. In the current study, we propose a new concept for anti-inflammatory treatment based on a selective acidic mammalian chitinase (AMCase) inhibitor. The functions of chitinases remain unclear, but they have been shown to be implicated in the pathology of various inflammatory disorders regarding the lung (asthma, idiopathic pulmonary fibrosis) and gastrointestinal tract (IBD and colon cancer).

Potent but transient immunosuppression of T-cells is a general feature of CD71 erythroid cells.

CD71 erythroid cells (CECs) have been recently recognized in both neonates and cancer patients as potent immunoregulatory cells. Here, we show that in mice early-stage CECs expand in anemia, have high levels of arginase 2 (ARG2) and reactive oxygen species (ROS). In the spleens of anemic mice, CECs expansion-induced -arginine depletion suppresses T-cell responses.

A Novel Oral Arginase 1/2 Inhibitor Enhances the Antitumor Effect of PD-1 Inhibition in Murine Experimental Gliomas by Altering the Immunosuppressive Environment.

Glioblastomas (GBM) are the common and aggressive primary brain tumors that are incurable by conventional therapies. Immunotherapy with immune checkpoint inhibitors is not effective in GBM patients due to the highly immunosuppressive tumor microenvironment (TME) restraining the infiltration and activation of cytotoxic T cells. Clinical and experimental studies showed the upregulation of expression of the arginase 1 and 2 (ARG1 and ARG2, respectively) in murine and human GBMs.

Chitinases and Chitinase-Like Proteins as Therapeutic Targets in Inflammatory Diseases, with a Special Focus on Inflammatory Bowel Diseases.

Chitinases belong to the evolutionarily conserved glycosyl hydrolase family 18 (GH18). They catalyze degradation of chitin to -acetylglucosamine by hydrolysis of the β-(1-4)-glycosidic bonds. Although mammals do not synthesize chitin, they possess two enzymatically active chitinases, i.

Towards vaccine against toxoplasmosis: evaluation of the immunogenic and protective activity of recombinant ROP5 and ROP18 Toxoplasma gondii proteins.

Toxoplasmosis is one of the most common parasitic infections worldwide. An effective vaccine against human and animal toxoplasmosis is still needed to control this parasitosis. The polymorphic rhoptry proteins, ROP5 and ROP18, secreted by Toxoplasma gondii during the invasion of the host cell have been recently considered as promising vaccine antigens, as they appear to be the major determinants of T.

Phytoecdysteroids as modulators of the Toxoplasma gondii growth rate in human and mouse cells.

Background: Searching for new effective drugs against human and animal toxoplasmosis we decided to test the anti-Toxoplasma potential of phytoecdysteroids (α-ecdysone and 20-hydroxyecdysone) characterized by the pleiotropic activity on mammalian organisms including the enhancement of host's anti-parasitic defence. This objective was accomplished by the in vitro evaluation of T. gondii growth in phytoecdysteroid-treated immunocompetent cells of selected hosts: humans and two strains of inbred mice with genetically determined different susceptibility to toxoplasmosis.

Human toxoplasmosis: a comparative evaluation of the diagnostic potential of recombinant Toxoplasma gondii ROP5 and ROP18 antigens.

Toxoplasmosis is one of the most common parasitic diseases worldwide and it poses a serious challenge regarding prevention, diagnosis and therapy. The commonly used diagnostic methods are mostly based on the detection of specific antibodies in sera. Since they are not always accurate enough and do not allow precise definition of the phase of the Toxoplasma gondii infection, there is an urgent need to find specific molecular markers of acute or chronic infection stages.

Toxoplasma gondii: cloning, expression and immunoreactivity of recombinant ROP5 and ROP18 antigens.

Early diagnosis and determining the infective stage are critical for effective therapy of toxoplasmosis. Owing to the progress in biotechnology, commonly used native, non-standardized diagnostic antigens should be replaced by genetically engineered antigens. The recombinant proteins are also promising components of subunit vaccines against Toxoplasma gondii infections.

Veterinary vaccines against toxoplasmosis.

Toxoplasma gondii is a cosmopolitan protozoan parasite that infects a wide range of mammal and bird species. Common infection leads to high economic (e.g.

Natural microbiota in viral and helminth infections. Addendum to: Personalized vaccination. II. The role of natural microbiota in a vaccine-induced immunity.

Numerous original and review papers have emerged over recent years concerning the natural microbiota and its interaction with the mammal host's body. This addendum supplements in short our previous review article on the role of microbiota in the host immunity paying, particular attention to such essential aspects as the composition and role of gut microbiota in viral infections as well as the interplay between the microbiota and the macrofauna inhabiting the mammalian gastrointestinal tract. The host immune system, commensal microbiota and macrofauna are elements of an integrated system in which the relationships are bidirectional.

Functional exhaustion of T lymphocytes in chronic toxoplasmosis.

One of the most characteristic features of many intracellular parasite infections is their chronicity indicating that the host immune system is not capable of eradicating the pathogen. Toxoplasma gondii is the most successful parasite worldwide, infecting an extraordinarily broad range of hosts (endothermic animals and humans) and almost all cell types. Recent studies have revealed that in late chronic toxoplasmosis CD8+ T lymphocytes become progressively exhausted and this dysfunction is suggested to be responsible for the reactivation of latent infection, which may result in a life-threatening disease in immunocompromised individuals (e.

Toxoplasma gondii--an amazing parasite. A comment to the article of Koshy A.A. et al. "Toxoplasma co-opts host cells it does not invade".

Ubiquitous parasite of humans and endothermic animals Toxoplasma gondii (type Apicomplexa), identified by Nicolle and Manceaux over 100 years ago, is still an object of numerous extensive studies bringing very interesting and often even surprising observations as that announced in the title [1].