Rivas López, Luis Ignacio
91 837 3112 Extension: 4232/4235
The phospholipid matrix of biological membranes acts not only as a physical scaffold for the rest of membrane components, but also as permeability barrier to preserve the intracellular or intraorganellar homeostasis. As the membrane structure is largely preserved throughout the full range of living organisms, there is a paucity of drugs targeting the lipid matrix, limited nowadays to polyenes and some membrane-active peptides. In contrast, innate immunity, present in all pluricellular organisms, strongly relies on membrane-active peptides, acting as a first chemical barrier to curb incipient pathogen invasion. Furthermore, some proteins with the capacity to translocate across membranes work as transcellular signal transductionpathways, independent of devoted specific translocator/transporters.
According to the class of interaction established between peptides and the membrane, we may arbitrarily classify them into three major groups:
Peptides whose microbicidal activity lead to the irreversible permeation of the cell membrane of the target cell, achieved through massive peptide insertion into the phospholipid matrix.
In general, they are strongly cationic peptides with intrinsic amphipatic structures or adopted after insertion into the pathogen membrane. Their selectivity of action relies on the exposure of anionic phospholipids of the cell membrane to the external medium, a trait of prokaryotes and lower eukaryotes, but not of higher eukaryotes where they are confined into the cytoplasmic leaflet, precluding their interaction with antimicrobial peptides. Two chemotherapeutical advantages for these peptides are their activity on a wide spectrum of pathogens, and the low rate of resistance induction, as it will require dramatic changes in the phospholipid composition of the membrane, with simultaneous effect on the activity of the enzymatic and transport systems located there.
Antimicrobial peptides acting on intracellular targets.
Their interaction with the membrane is reversible and transitory, imposed by their translocation across the lipid bilayer in order to gain access to their intracellular destination; membrane damage is mild and transitory.
Cell penetrating peptides.
Their interaction with membranes is similar to the previous group; nonetheless an intrinsic microbicidal activity is not mandatory. Their potentiality in chemotherapy relies on their role as peptide vehicles to transport across the membrane a variety of molecules associated or conjugated to them, including biopolymers, nanoparticles, quantum dots…, otherwise impermeable to it, regardless of canonical transporters/translocators, widening the repertoire of therapeutic molecules into peptides, proteins or nucleic acids. Additionally, when fused to import sequence for organelles, they allocate the cargo molecule into a specific intracellular location, avoiding potential side-effects due to spurious interaction outside the final organelle.
Research in our group is focused on the assay, design and production of membrane-active peptides for chemotherapeutical applications on two pathogens mainly, Acinetobacter baumannii, a Gram negative bacteria and the protozoon Leishmania sp. Chemotherapy against both pathogens underwent a rapid decline in efficacy due to resistance and the paucityof drugs available. Our quest is to discover new active leads on these pathogens , preferentially peptides, definition of their mechanism of action, and structural optimization, as well as the design of new administration pathways based on peptide vehicles for new and current clinical drugs.