Unit:
Department of PharmacyLibrary of the School of Science
Author:
Tzitzoglaki Christina
Dissertation committee:
Κολοκούρης Αντώνιος Αναπλ. Καθηγητής Τμήμα Φαρμακευτικης ΕΚΠΑ
Τσοτίνης Ανδρέας Καθηγητής Τμήμα Φαρμακευτικης ΕΚΠΑ
Μαράκος Παναγιώτης Καθηγητής Τμήμα Φαρμακευτικης ΕΚΠΑ
Μικρος Εμμανουήλ Καθηγητής Τμήμα Φαρμακευτικης ΕΚΠΑ
Παπαναστασίου Ιωάννης Επίκουρος Καθηγητής Τμήμα Φαρμακευτικης ΕΚΠΑ
Μαυρομούστακος Θωμάς Καθηγητής Τμήμα Χημείας ΕΚΠΑ
Busath David, Καθηγητής Department of Physiology and Biophysics , Brigham Young University, USA
Original Title:
Molecular basis of inhibition and resistance of the influenza M2 ion channel by aminoadamantane drugs and discovery of novel resistance-breaking inhibitors targeting the mutant M2 proton channel
Translated title:
Molecular basis of inhibition and resistance of the influenza M2 ion channel by aminoadamantane drugs and discovery of novel resistance-breaking inhibitors targeting the mutant M2 proton channel
Summary:
Amantadine (Amt (1)) and rimantadine (Rim (2)) are blockers of proton transport by influenza A virus Μ2 ion channel protein, and approved as prophylactics and therapeutics against influenza A wild type (WT) viruses. However, since 2005, the amantadine-insensitive Ser-to-Asn mutation at position 31 (S31N) in M2 protein has become globally prevalent, abrogating the clinical usefulness of amantadine3,4and possibly other previously reported M2 inhibitors. Thus, new agents are needed to combat drug-resistant strains of influenza.
The primary binding site of amantadine and rimantadine is the transmembrane domain lumen (TM, amino acids 22-46) in the four-helix bundle of tetrameric M2 WT, that forms the proton transport path. According to high resolution structures from X-ray and solid state NMR (ssNMR) experiments published between 2008-2011 by Tim Cross, William DeGrado, and Mei Hong in the highest impact factor Journals i.e., Nature, JACS etc, the M2TM protein channel is blocked by amantadine and rimantadine via a pore-binding mechanism. The adamantyl cage in these molecules is tightly contacted on all sides by V27 and A30 side chains, producing a steric occlusion of proton transport and thereby preventing the continuation of the viral life cycle. The ssNMR results also demonstrated that the ammonium group of these drugs is pointing towards the four H37 residues at the C-end. 9 This orientation can be stabilized only through hydrogen bonds between the ligand and (a) with water molecules in the channel lumen between the imidazoles of H37 and the ligand and (b) possibly with A30 carbonyls in the vicinity, according to experimental and molecular dynamics (MD) simulations data. Provided that M2TM is a minimal model for M2 binding, these experimental high resolution structures can be used for the prediction of new ligands binding more effectively to the M2TM pore for example through MD simulations19 or more precisely by binding free energy calculations.
Main subject category:
Science
Other subject categories:
Health Sciences
Keywords:
Amantadine, rimantadine, ion channel protein, influenza A, Ser-to-Asn mutation
