Pharmaceutical Biophysics
The Pharmaceutical Biophysics Group, comprising Professor Jayne Lawrence, Dr David Barlow, Dr Alex Drake, Dr Cécile Dreiss, Dr Richard Harvey, Dr James Mason, Dr Laila Kudsiova and Emeritus Professor Peter Quinn, aims to secure an understanding at the molecular level of the physicochemical and biological properties of small and macromolecules, lipid membrane systems and macromolecular drugs and drug delivery systems, through the combined application of advanced analytical techniques, including computer modelling, FT-IR, circular dichroism, Raman spectroscopy, static and dynamic light scattering, rheometry and dilute solution viscometry, atomic force microscopy, X-ray diffraction, small angle neutron scattering, neutron reflectivity and both liquid and solid-state NMR.
The group applies scientific principles and analytical techniques to identify, characterise and quantify biological molecules. This work is applied in both the kinetic and equilibrated states to the health related fields, drug disposition and metabolism, biochemical endocrinology, clinical chemistry and evidential analysis.
Dr Dreiss' research focuses on characterising and understanding self-assembly processes in a range of polymeric and colloidal systems. Self-organisation driven by electrostatic interactions, hydrogen bonds or hydrophobic interactions is ubiquitous in nature and determines the mechanical and functional properties of materials. Projects in Dr Dreiss group, aim at understanding the principles of this self-organisation and building-up relationships between structure on the nanoscale and the macroscopic properties which result from it, such as rheology.
Small-angle neutron and X-ray scattering are used to probe the structure of systems of interest, covering a wide range of length scales down to the angstrom-size. The method of contrast-variation (with neutrons), which uses selective deuteration, offers the unique possibility of alternately hiding or highlighting constituents of interest, a key-attribute in these complex multi-component systems.
Current projects and systems of interest include:
Wormlike micelles formed in mixtures of surfactants; effect of oil encapsulation and additives; interaction with hydrophobically modified biopolymers;
Polymeric micelles and their potential as drug carriers; change in aggregates structure in the presence of drug; effect of pH and temperature; complexation with cyclodextrin and competitive interactions;
Oligomerisation and fibrillation of amyloidogenic proteins and peptides: structure, kinetic pathway and mechanism of formation
Biopolymers gels from gelatin and mixtures with natural polymers; competition between physical and chemical gelation (enzymatic crosslinking); applications in tissue engineering
Dr Barlow research over recent years has been primarily concerned with structural and computational studies of drugs, and drug and gene delivery systems. These studies have included: detailed characterisation of the molecular architectures and membrane interactions of gene delivery vehicles; development of novel software for modelling biological membrane structure; development of expert systems approaches for drug discovery and modelling of drug delivery systems; and the development of novel systems for heterologous expression of eukaryotic integral membrane proteins.
Topics:
Bio-informatics and chemo-informatics of Traditional Chinese Medicines;
gene therapy of mitochondrial disorders;
neutron reflectivity and SANS studies of drug delivery systems and model membranes.
The goal of Dr Mason's research is to understand how the dynamic composition of biological membranes influences how organisms respond to their environments. In particular, we are interested in how they interact with molecules designed to disrupt, disorder and/or cross their membranes.
Our approach is to obtain a fundamental, molecular level understanding of the effect of peptides or other drugs on the structure, organisation and dynamics of model membranes designed to closely mimic the properties of key target membranes in nature. This information is then put into context by relating the observed behaviour of these compounds in living cells to their biophysical features. In this way we are beginning to understand the role that biological membranes play in diverse areas including bacterial and malarial infections, genetic diseases and cancer metastasis.
Understanding the interactions of peptides with membranes at the molecular level allows us to modulate the activity of the peptide, leading to enhanced activity and reduced cellular toxicity. Membrane active peptides can have a variety of roles but we are particularly interested in peptides that have antibiotic properties or can be used as vectors for nucleic acids to deliver gene therapeutics to mammalian cells. By studying natural and designed antibiotic peptides we aim to obtain rules for the rational design of antibiotics that are active against bacteria such as Pseudomonas aeruginosa, fungi and the malaria parasite Plasmodium falciparum. Histidine rich amphipathic peptides can also be highly efficient gene or siRNA delivery vehicles. We have shown that such peptides are more efficient vectors when they can interact with negatively charged lipids in the target cell membrane. We aim to understand this interaction in more detail so that it can be exploited for biotechnological or therapeutic applications.The research uses a wide range of biophysical methods in conjunction with in silico molecular dynamics simulations which provide data which we incorporate in an overall view, together with in vitro activity assays, transcript and metabolomic profiling of how both bacteria and host cells respond to being challenged by the peptides.
Specific research themes include:
- Application of solid-state NMR methodologies to peptide structure and membrane dynamics
- Quantification of peptide secondary structure in membrane environments using Circular Dichroism (CD) and other optical spectroscopy methods
- The role of conformational flexibility in the mechanism of action and toxicity of cationic alpha-helical amphipathic antimicrobials
- The role of membrane interactions in the activity of human beta defensin-2 (hBD-2)
- Manipulating peptide-membrane interactions to enhance peptide mediated nucleic acid delivery and develop safe and efficient non-viral vectors
- Linking the biophysical activities of antimicrobial peptides to a molecular genetic view of challenged bacteria and P. falciparum
- Linking biophysical measurements to predictive in silico molecular dynamics simulations
- Development of Magic Angle Spinning (MAS) NMR approaches to metabolomic profiling
Specific areas of interest include:
- The role of aminoacyl lipids in the structure and function of bacterial membranes in relation to antimicrobial drug resistance.
- The effect of antimicrobial peptides and polymers on aggregation behaviour and toxicity of lipopolysaccharides.
- Physico-chemical studies of behaviour of charged and neutral lipids and surfactants in the binary and ternary mixtures commonly used in drug delivery vehicles.
