Granja / Montenegro / García-Fandiño

One of the great challenges of modern synthetic organic chemistry it is the construction of complex structures with a precise control of its three-dimensional shape, functional groups and components in a reduced time and number of steps, through a low cost and environmentally friendly way.

From our point of view, the efficient and precise construction of these complex structures can only be achieved through molecular self-assembly processes. These strategies provide structures (supramolecular complexes) that are beyond the molecule, in which specially designed small molecules are joined together by non-covalent bonds, such as hydrogen bonds, halogen bonds, van der Waals, etc. Organometallic and coordination chemistry can also play a key role in these processes derived form their unique ability to organize around the metal center different molecules (ligands) with a variety of geometries. Additionally, they also allow the preparation of novel catalysts for the development of new chemical transformations.

On the other hand, these supramolecular structures can be used as "intelligent" materials that form the active species only under some specific conditions, i. e. at the membrane of a bacteria or of a tumor cell. Similarly to their natural counterparts (the antimicrobial peptides), these synthetic antimicrobial / antitumoral mimetics could be built from simpler components with low toxicity, and act by a molecular self-assembly process at the bacteria or tumor cell membrane, disrupting its properties and causing its death. A detailed understanding of the molecular details of the membrane permeabilization process would allow the rational design of new molecules with the same mechanism of action, but with improved activity, selectivity, and bioavailability. In that sense, computational multi-level simulations may provide the necessary bridges to achieve a complete understanding of the interaction processes.

Additionally, Javier Montenegro has obtained in 2015 the ERC Starting Grant, the most prestigious support in Europe for young scientists, in recognition of his project "Dynamic Cell Penetrating Peptides" (DYNAP).

The aim of DYNAP is to identify, at the molecular level, the minimal topological and structural motifs that govern the membrane translocation of short peptides. A covalent reversible bond strategy will be developed for the synthesis of self-adaptive penetrating peptides (adaptamers) for targeted delivery.

PEPTIDE NANOTUBES

Watch video "Peptide Nanotubes as Supramolecular drugs"

Watch video "α,γ-Peptide Nanotubes: a Computational Study"

The peptide nanotubes are a new class ofsupramolecular biomaterials formed by stacking cyclic peptides. These peptides are designed to adopt a planar conformation, disc or ring shape, in which all the amide groups of the peptide backbone (carbonyl and NH) are perpendicularly oriented to the plane of the ring. This conformation facilitate the formation of hydrogen bonds with other cyclic peptide subunits. In addition, all amino acid side chains are outwards projected modifying the surface characteristics of the tubular assembly. Therefore the nanotube formation can be achieved in different media and conditions with a precise control of their inner diameter. For the construction of these materials, the designed molecules contain the structural information that determines the conditions that lead to the nanotube formation and their properties.

One of the characteristics of nanotubes we are working in our research group, which makes them especially unique, is the option to modify its internal properties. This modification is achieved by the use of cyclic gamma-amino acids. The internal cavities of the nanotubes are 1-D world and, therefore, the molecules located inside the nanotube have different properties. All these characteristics should allow the efficient construction of peptide nanotubes with novel properties.

  Representations of the interactions of peptide nanotubes with the lipid bilayers.
 

This design control of both the internal and external characteristics of the nanotubes opens the opportunity, among others, to explore specific applications such nanotubes that interact with lipid membranes. Peptide nanotubes forming transmembrane channels efficiently transport alkaline ions, while other are parallel arranged to the lipid bilayer that destroy cellular membranes. We are studying this latter property in order to design new cytotoxic agents.

Recently we have also shown the formation of hybrid nanotubes (carbon/peptide) that combine the electronic properties and hardness of carbon nanotubes with the biocompatibility of the peptidic components.

             

Finally, we have developed a “DNA artificial nose” that allows the qualitative identification (smelling) of a variety of polynucleotides with single nucleobase resolution. The strategy is based on the amplification of differences in transmembrane transport properties across the membrane of a supramolecular complex formed by the oligonucleotide and designed transporter (Small, 2014, DOI: 10.1002/SMLL20140068).

DYNAMIC BONDS FOR MEMBRANE TRANSPORT

Watch video "Taking genetic engineering & therapy to the next level"

The plasma membrane is a dynamic barrier critical for the compartmentalization of biological processes and cellular homeostasis. However, the membrane barrier can be a formidable obstacle for the delivery of some probes and/or complex therapeutics, especially large macromolecules. Therefore, the development of novel strategies to cross the lipid bilayer and reach the cytosol of the cell is of great importance. One of the main goals of our group is the development of new carriers, by using dynamic covalent chemistry for the straightforward incorporation of hydrophobic tails to amphiphilic molecules. This methodology has been applied to polymers and peptides and has been successful for the delivery in several cell lines of interference RNA (siRNA), plasmids, or Cas9 ribonucleoprotein of the CRISPR system.