A Novel, Orally Bioavailable, Small-Molecule Inhibitor of PCSK9 With Significant Cholesterol-Lowering Properties In Vivo

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibits the clearance of low-density lipoprotein (LDL) cholesterol (LDL-C) from plasma by directly binding with the LDL receptor (LDLR) and sending the receptor for lysosomal degradation. As the interaction promotes elevated plasma LDL-C levels, and therefore a predisposition to...

The art and practice of systems biology in medicine: Mapping patterns of relationships

Systems biology has developed in recent years from a technology-driven enterprise to a new strategic tool in Life Sciences, particularly for innovative drug discovery and drug development. Combining the ultimate in systems phenotyping with in-depth investigations of biomolecular mechanisms will enable a revolution in our understanding of disease...

Putting pharmacogenetics into practice

Metabolism of ATP-binding cassette drug transporter inhibitors: Complicating factor for multidrug resistance.

Membrane transport proteins belonging to the ATP-binding cassette (ABC) family of transport proteins play a central role in the defence of organisms against toxic compounds, including anticancer drugs. However, for compounds that are designed to display a toxic effect, this defence system diminishes their effectiveness. This is typically the...

Rescuing drug discovery: In vivo systems pathology and systems pharmacology

The pharmaceutical industry is currently beleaguered by close scrutiny from the financial community, regulators and the general public. Productivity, in terms of new drug approvals, has generally been falling for almost a decade and the safety of a number of highly successful drugs has recently been brought into question. Here, we discuss...

Systems biology, connectivity and the future of medicine

The concept of systems-based strategies in medicine is emerging, with systems pathology guiding an understanding of the multidimensional aspects of disease system fingerprints and systems pharmacology providing insight into dynamic system responses upon (multiple) drug perturbations. Knowledge of the changes of system characteristics during...

Design and synthesis of novel N-acetylgalactosamine-terminated glycolipids for targeting of lipoproteins to the hepatic asialoglycoprotein receptor

A novel glycolipid has been prepared that contains a cluster glycoside with an unusually high affinity for the asialoglycoprotein receptor (ASGPr) and a bile acid moiety that mediates stable incorporation into lipidic particles. The glycolipid spontaneously associated with low-density lipoproteins (LDL) and high-density lipoproteins (HDL) within...

Design, synthesis, and evaluation of sugar amino acid based inhibitors of protein prenyl transferases PFT and PGGT-1

Eleven analogues of the C-terminal Ca1a2X motif found in natural substrates of the prenyl transferases PFT and PGGT-1 were synthesized and evaluated for their inhibition potency and selectivity against PFT and PGGT-1. Replacement of the central dipeptide part a1a 2 by a benzylated sugar amino acid resulted in a good and highly selective PFT...