Altering Metabolic Profiles of Drugs by Precision Deuteration 2: Discovery of a Deuterated Analog of Ivacaftor with Differentiated Pharmacokinetics for Clinical Development.

Ivacaftor is currently used for the treatment of cystic fibrosis as both monotherapy (Kalydeco; Vertex Pharmaceuticals, Boston, MA) and combination therapy with lumacaftor (Orkambi; Vertex Pharmaceuticals). Each therapy targets specific patient populations: Kalydeco treats patients carrying one of nine gating mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, whereas Orkambi treats patients homozygous for the F508del CFTR mutation. In this study, we explored the pharmacological and metabolic effects of precision deuteration chemistry on ivacaftor by synthesizing two novel deuterated ivacaftor analogs, CTP-656 (-ivacaftor) and -ivacaftor.

Zmynd15 encodes a histone deacetylase-dependent transcriptional repressor essential for spermiogenesis and male fertility.

Spermatogenesis is a complex process through which male germ line stem cells undergo a multi-step differentiation program and sequentially become spermatogonia, spermatocytes, spermatids, and eventually spermatozoa. In this process, transcription factors act as switches that precisely regulate the expression of genes that in turn control the developmental program of male germ cells. Transcription factors identified to be essential for normal haploid gene expression all display transcription-activating effects and thus serve as the "on" switch for haploid gene expression.

Critical roles for CCR2 and MCP-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites.

Monocyte recruitment to sites of inflammation is regulated by members of the chemokine family of chemotactic cytokines. However, the mechanisms that govern the migration of monocytes from bone marrow to blood and from blood to inflamed tissues are not well understood. Here we report that CC chemokine receptor 2 (CCR2) is highly expressed on a subpopulation of blood monocytes whose numbers are markedly decreased in CCR2(-/-) mice.

Targeted disruption of the scavenger receptor and chemokine CXCL16 accelerates atherosclerosis.

Background: The uptake of oxidized low-density lipoprotein (OxLDL) by macrophage scavenger receptors is thought to be a key process in the formation of foam cells, the hallmark of early atherosclerotic lesions. CXCL16/scavenger receptor for phosphatidylserine and OxLDL is a multifunctional chemokine that exhibits scavenger receptor activity toward oxidized lipids in a membrane-bound configuration and may be shed to serve as a chemoattractant for T helper 1-polarized T lymphocytes. These properties, as well as the expression of CXCL16 in human and mouse atheroma, suggest that CXCL16 plays a role in atherosclerosis.

Transient role for CD1d-restricted natural killer T cells in the formation of atherosclerotic lesions.

Objective: CD1d-restricted natural killer T (NKT) cells are reported to play a proatherogenic role in the development of atherosclerosis. However, the contribution of NKT cells to mature lesion formation and the effector mechanisms through which they act are unknown.

Methods And Results: We measured lesion size in CD1d-null (CD1d-/-) mice on the low-density lipoprotein (LDL) receptor-deficient (LDLR-/-) genetic background after 4, 8, and 12 weeks of feeding on a Western diet.

Characterization of the human beta-globin downstream promoter region.

The human beta-globin gene is abundantly expressed specifically in adult erythroid cells. Stage-specific transcription is regulated principally by promoter proximal cis-regulatory elements. The basal promoter contains a non-canonical TATA-like motif as well as an initiator element.