Focco van den Akker, PhD

Associate Professor
Department of Biochemistry
School of Medicine

Research Information

Research Interests

The overall goal of my research is to elucidate the molecular intricacies of enzyme mechanism and receptor activation and using that knowledge to develop inhibitors and activators for pharmaceutical purposes. Our projects range from antibiotic resistance related proteins (such as bacterial beta-lactamases, penicillin binding proteins, and lytic transglycosylases) to cell signaling proteins such as guanylyl cyclases (for blood pressure, vision, and bone growth). Our lab employs state of the art multi-disciplinary biophysical, biochemical, crystallographic, computational, screening, molecular biology, and cell biology techniques.

Research Projects

van den Akker Lab Website

Postdoc position available in the van den Akker lab; contact focco.vandenakker@case.edu

LAB's STRUCTURES WITH PHARMACEUTICAL RELEVANCE

Cardiovascular diseases
A cool heme-mimetic at work! (Click for coordinates or viewer) Collaboration with BAYER HEALTHCARE; cinaciguat is in clinical trials for acute decompensated heart failure


The lytic transglycosylase from Campylobacter jejuni, a doughnut-shaped protein that degrades peptidoglycan (Click for coordinates or viewer) Collaboration with Jun Lin (U. of Tennessee).

Infectious diseases
Fighting antibiotic resistance (Click for coordinates or viewer) Collaboration with clinician researchers, biochemistists, microbiologists, and pharmaceutical industry; a new diazabicyclooctane beta-lactamase inhibitor

Trying to improve existing drugs (Click for coordinates or viewer) Collaboration with clinician researchers, medicinal chemists, and spectroscopists; structure-based designed tazobactam analog with improved inhibitor intermediate properties


The main focus in the van den Akker lab is on the molecular basis of antibiotic resistance. The projects entail the structure-function studies of bacterial enzymes involved in the metabolism of the peptidoglycan, a key bacterial drug target. We are investigating how bacteria become resistant to antibiotics/inhibitors targeting the peptidoglycan, as well as develop novel compounds. We employ a novel synergistic Raman/X-ray crystallographic approach to allowed detailed time-dependence and structural information of intermediate formation of inhibitors and antibiotics. In addition, we employ Molecular Dynamics simulations and fragment-based screening efforts to gain new insights and develop tool compounds. We have used this information to improve inhibition aspects of clinical and novel inhibitors via the rational drug design cycle. Our structure-based drug design efforts to combat antibiotic resistance involves clinician researchers, a medicinal chemist team, and structural biologists as well as pharmaceutical industry connections (this project is in collaboration with Drs. Bonomo, Carey, Buynak, Prati, Lin, Mobashery, Papp-Wallace, and others).

The guanylyl cyclases can be either membrane bound or soluble and are activated by either peptides or nitric oxide (NO), respectively. Our lab has recently published on new insights regarding the dimerization, NO and BAY58-2667/cinaciguat activation of the soluble guanylyl cyclase. Our structural studies are also aimed at developing new activators to treat cardiovascular diseases such as heart-failure, hypertension, erectile dysfunction, and atherosclerosis and involves a pre-clinical collaboration with pharmaceutical industry.

Additional collaborations. We have additional crystallographic and/or in silico drug screening collaborations with the labs of Sam Mesiano, Arne Rietsch, Jonathan Stamler, Dennis Stuehr, David Buchner, David Wald. In addition, we collaborate and receive funding from five pharmaceutical companies.

Publications

View Publications

Education

PhD
University of Washington
Post Doc
Lerner Research Institute, Cleveland Clinic