Figure 1

Contact person: Dr. Markus Weingarth
(Bloembergen NMR building)

Introduction

Many drugs need to enter the cell interior to be active. However, to their large size or high net charge, many drugs can not cross biological cell membranes by themselves. To get into the cell nevertheless, many drugs hence have to rely on supramolecular drug delivery systems.

Such nano-scale drug delivery systems need to be smart and tunable materials, since many hurdles have to be overcome to get a drug into cell (Figure 1). Once in the cell interior smart drug carriers need to be sensitive to a stimulus that triggers the release of the drug. It is for example imaginable to design a drug vector that only releases its cargo once it feels the acidic environment of a tumor cell.

Such smart drug vectors can be self-assembled from peptides, which feature an excellent biocompatibility and, in particular, are straightforward to tune and optimize by changing the amino acid sequence. However, to precisely steer and program the biophysical and pharmaceutical profile of peptide-based drug vectors, a precise knowledge of their supramolecular code is mandatory. Yet, peptide assemblies are often not amenable to most high-resolution methods and hence poorly understood at the molecular level. Without atomic data, the design of novel supramolecular peptide vaccines must rely on empirical rule-based approaches as well as a fair degree of serendipity.

Figure 2

We have recently shown [1] that the integration of solid-state NMR with multi-scale molecular dynamics simulations gives access to high-resolution structures of supramolecular peptide-based drug vectors (Figure 2). 

Goals

In the proposed master project, the student will investigate the supramolecular structure and dynamics of a peptide-based drug vector for gene therapy. With the atomic level data, the student will rationally design the biophysical profile (such as drug binding & retention) of the carrier.

The project involves

  • Preparation of drug vectors from self-assembling peptides
  • Solid-state NMR characterisation of drug vectors
  • Integration solid-state NMR data with multi-scale molecular dynamics simulations to obtain supramolecular structures of drug vectors

 

[1] Rad Malekshahi, M., Visscher. K.M., Rodrigues J.P.G.L.M., de Vries, R., Hennink, W.E.,  Baldus, M., Bonvin A.M.J.J., Mastrobattista E., Weingarth. M. (2015)  J. Am. Chem. Soc., 137, 7775, The supramolecular organization of a peptide based nanocarrier at high molecular detail.