National Physical Laboratory

Research

Fibroblast BoxThe Centre set out to develop and improve underlying measurement science and analysis tools required to obtain reliable links between polypeptide sequence, structure and function. Our main approach is the use of approximated structural continuum models that would allow interconversions between different time and length scales spanning related biophysical phenomena. 

Strategically important areas as defined by European Commission and European Metrology Research Programmes are chosen to provide the application focus and context for the research programme.

Relevant topics share common structure-function problems with similar measurement challenges, and are as follows:


Molecular control of anti-microbial function and resistance:

Antimicrobial peptides (AMPs) are universal host-defence agents of innate immune systems found in all multicellular organisms. The peptides compromise the integrity of the cell membrane either by forming membrane pores or by inducing non-lamellar structures. With increases in antibiotic resistance worldwide, the most pressing challenge is to develop novel classes of antimicrobial agents. AMPs are main candidates for antimicrobial intervention in the post-antibiotic era. Research using new approaches to validate novel AMP therapeutics, and new approaches to delivery and improved stability, are anticipated to result in an increased range of peptide therapeutics available in clinic.


Membrane fusion as molecular basis of viral epidemics:

Fusogenic peptides are critical structural components of viral proteins, which insert into lipid bilayers and act as anchors, bringing two lipid bilayers into proximity and thus promoting infection. For example, a key event in the HIV-1 lifecycle is the fusion of the viral membrane with that of the cell, allowing entry of the viral genome and associated proteins. The fusion event is promoted by gp41, one of two glycoproteins which form the envelope protein complex on the exterior of the virion. gp41 undergoes a series of structural transitions, each of which can be measured and monitored and is necessary for fusion and hence for viral infectivity.


Membrane transduction as interfacial modality for cell targeting:

Selective delivery of therapeutic cargo into the cell can be achieved by specific and non-specific peptide-mediated transductions. The process of selective drug targeting has always proved a major challenge, which severely limits the palette of possible drug molecules. Mediated by cell-penetrating peptides or integrin antagonists, therapeutic cargo can be delivered into an intracellular target circumventing the restrictions normally imposed by cellular membranes. However, transduction mechanisms allowing molecular transport between external and internal milieu as well as principles of discriminative targeting remain to be revealed by precise multimodal measurements including structural and imaging techniques.  


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