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The Molecular Recognition Section of NIDDK announces the availability of a novel triazole-based probes, structures which act as antagonists at human P2Y₁₄ receptors. Although the physiologic functions of this receptor remain undefined, recently it has been strongly implicated in immune and inflammatory responses. Prior work with a 4,7-disubstituted 2 naphthoic acid derivative (PPTN) established the ability to inhibit chemotaxis of human neutrophils in the lung and kidney.

Engineered chimeric antigen receptors (CARs) that are expressed in cytotoxic T cells and natural killer (NK) cells have been used to specifically target tumor cells. However, CAR-T and CAR-NK cells are still subject to down regulation by their inhibitory receptors after injection into patients.

The technology describes the composition of small molecule compounds that are antagonists of the P2Y14 receptor. Also provided are methods of using the compounds, including a method of treating a disorder, such as inflammation, diabetes, insulin resistance, hyperglycemia, a lipid disorder, obesity, a condition associated with metabolic syndrome, and asthma, and a method of antagonizing P2Y14 receptor activity in a cell.

This technology includes the use of the small molecule metarrestin (ML246) for the treatment of several types of pancreatic cancer. A subcellular structure called the perinucleolar compartment (PNC) is frequently found in metastatic tumors and cancer stem cells. Reduction of PNC prevalence followed by medicinal chemistry was used to identify metarrestin as a compound that reduces PNC prevalence without significantly impacting cell viability. In vitro and in vivo animal work have demonstrated desirable pharmacokinetic properties as well as a reduction in metastatic burden and extended survival.

Monoclonal antibodies (mAbs) have become a mainstay of therapy for many cancers. However, antibody therapy is not completely effective in some applications due to loss of the target surface antigen on cancer cells. Such mAb-induced “escape variants” are no longer sensitive to the therapeutic mAb therapy. It was observed that the escape variants carried covalently bound complement activation fragments, especially C3d. NIH inventors have generated several C3d-specific mouse and rabbit monoclonal antibodies to re-target cells that have escaped from mAb therapy.

This technology includes the identification and use of heterocyclic alcohol compounds, including RITA and N-BIC, for the treatment of SULT1A1-expression cancers. A high-throughput screen (qHTS) was performed using >1,000 caner cell lines identified a compound called YC-1 (also called Lificiguat) that is effective across cancer cell types that express the phase 2 detoxifying enzyme SULT1A1.

This technology includes a new method to induce recombinant protein expression in E. coli through the activating the SoxS promoter by molecular oxygen. We previously discovered that the SoxRS regulon of E. coli is activated in response to elevated dissolved oxygen concentration mainly to protect the bacteria from possible oxygen damage. We hypothesized that the 16-fold increase in the expression of this regulon make it possible candidate for inducing the expression of recombinant proteins.

This technology includes a strategy to target tumor cells that lost antigen following reaction with a therapeutic antibody by targeting the complement component C3d that has been deposited on target cells by the primary antibody. We previously generated a C3d-specific mouse/human chimeric antibody called C8xi and obtained proof of principle for the approach in two preclinical models. Here we summarize the generation of a new set of C3d targeting antibodies.

This invention provides a novel family of acylthiols and uses thereof. More specifically, this invention provides effective inhibitors of HIV that selectively target its highly conserved nucleocapsid protein (NCp7) by interacting with metal chelating structures of a zinc finger-containing protein. Because of the mutationally intolerant nature of NCp7, drug resistance is much less likely to occur with compounds attacking this target.

AAV vectors offer unique advantages in gene therapy applications. Studies have shown that these replication deficient parvovirus vectors can deliver DNA to specific tissues and confer long-term transgene expression in a variety of systems. Although many studies have looked at the tissue-specific expression elicited by each of the AAV serotypes, a true understanding of how AAV transduces these tissues is still unclear. Of the large AAV family, only a few receptors or co-receptors have been identified.