Cholesterol: the good, the bad, and the ugly - therapeutic targets for the treatment of dyslipidemia.

Maintaining cholesterol and triglyceride (TG) levels within healthy limits is critical for decreasing the risk of heart disease. Dyslipidemia refers to the abnormal levels of lipids in the blood, including low high-density lipoprotein cholesterol (HDL-C), also known as good cholesterol, high low-density lipoprotein cholesterol (LDL-C), also known as bad cholesterol, and/or high TG levels that contribute to the development and progression of atherosclerosis. In this article we reviewed some of the current therapeutic targets for the treatment of dyslipidemia, with a primary focus on endothelial lipase and lecithin cholesterol acyl transferase for raising HDL-C, and the proprotein convertase subtilisin-like kexin type 9 (PCSK9), microsomal triglyceride transfer protein, and the messenger RNA of apolipoprotein B for lowering LDL-C.

Design, synthesis, and biological evaluation of peptidomimetic inhibitors of factor XIa as novel anticoagulants.

Human coagulation factor XIa (FXIa), a serine protease activated by site-specific cleavage of factor XI by thrombin, FXIIa, or autoactivation, is a critical enzyme in the amplification phase of the coagulation cascade. To investigate the potential of FXIa inhibitors as safe anticoagulants, a series of potent, selective peptidomimetic inhibitors of FXIa were designed and synthesized. Some of these inhibitors showed low nanomolar FXIa inhibitory activity with >1000-fold FXa selectivity and >100-fold thrombin selectivity.

Synthesis, SAR exploration, and X-ray crystal structures of factor XIa inhibitors containing an alpha-ketothiazole arginine.

Using an alpha-ketothiazole arginine moiety as a key recognition element, a series of small peptidomimetic molecules was designed and synthesized, and their co-crystal structures with factor XIa were studied in an effort to develop smaller, less peptidic inhibitors as antithrombotic agents.

Mutation of surface residues to promote crystallization of activated factor XI as a complex with benzamidine: an essential step for the iterative structure-based design of factor XI inhibitors.

Activated factor XI (FXIa) is a key enzyme in the amplification phase of the blood-coagulation cascade. Thus, a selective FXIa inhibitor may have lesser bleeding liabilities and provide a safe alternative for antithrombosis therapy to available drugs on the market. In a previous report, the crystal structures of the catalytic domain of FXIa (rhFXI(370-607)) in complex with various ecotin mutants have been described.

Structural and mutational analyses of the molecular interactions between the catalytic domain of factor XIa and the Kunitz protease inhibitor domain of protease nexin 2.

Factor XIa (FXIa) is a serine protease important for initiating the intrinsic pathway of blood coagulation. Protease nexin 2 (PN2) is a Kunitz-type protease inhibitor secreted by activated platelets and a physiologically important inhibitor of FXIa. Inhibition of FXIa by PN2 requires interactions between the two proteins that are confined to the catalytic domain of the enzyme and the Kunitz protease inhibitor (KPI) domain of PN2.

Crystal structures of the FXIa catalytic domain in complex with ecotin mutants reveal substrate-like interactions.

Thrombosis can lead to life-threatening conditions such as acute myocardial infarction, pulmonary embolism, and stroke. Although commonly used anti-coagulant drugs, such as low molecular weight heparin and warfarin, are effective, they carry a significant risk of inducing severe bleeding complications, and there is a need for safer drugs. Activated Factor XI (FXIa) is a key enzyme in the amplification phase of the coagulation cascade.

Cloning, expression, and initial characterization of a novel cytokine-like gene family.

We report the identification and characterization of a novel cytokine-like gene family using structure-based methods to search for novel four-helix-bundle cytokines in genomics databases. There are four genes in this family, FAM3A, FAM3B, FAM3C, and FAM3D, each encoding a protein (224-235 amino acids) with a hydrophobic leader sequence. Northern analysis indicates that FAM3B is highly expressed in pancreas, FAM3D in placenta, and FAM3A and FAM3C in almost all tissues.