How Valinomycin Ionophores Enter and Transport K⁺ across Model Lipid Bilayer Membranes

Abstract

Valinomycin, a cyclic peptide, was incorporated into a biomimetic lipid membrane tethered to the surface of a gold (111) electrode. Electrochemical impedance spectroscopy was used to study the ionophore properties of the peptide, and polarization modulation infrared reflection absorption spectroscopy was employed to determine the conformation and orientation of valinomycin in the membrane. The combination of these two techniques provided unique information about the ionophore mechanism where valinomycin transports ions across the membrane by creating a complex with potassium ions and forming an ion pair with a counter anion. The ion pair resides within the hydrophobic fragment of the membrane and adopts a small angle of ∼22° with respect to the surface normal. This novel study provides new insights explaining the valinomycin ion transport mechanism in model biological membranes.

Therapeutic Potential of Exploiting Autophagy Cascade Against Coronavirus Infection

“…For example, mTORC1 positively regulates replication of a New World hantavirus -Andes virus (ANDV), as treatment with a FDA-approved rapamycin analog temsirolimus (CCI-779) significantly inhibits viral protein expression and virion release (McNulty et al, 2013). In contrast, mTORC1 blocks hepatitis C virus (HCV) replication through Unc-51 Keyaerts et al, 2004Keyaerts et al, , 2009Mauthe et al, 2018;Hoffmann et al, 2020b;Liu et al, 2020;Schrezenmeier and Dorner, 2020;Wang et al, 2020 Rapamycin/ Sirolimus* Activates autophagy by inhibiting mTORC1 Reduces infection of MERS-CoV, PEDV and SARS-CoV-2 Dowling et al, 2010;Kindrachuk et al, 2015;Gassen et al, 2020;Lin et al, 2020 Wu et al, 2004;Smith and Blaylock, 2007;Rakovic et al, 2010;Gassen et al, 2019;Shen et al, 2019;Su et al, 2019;Sandler et al, 2020 like autophagy activating kinase ULK1 activation, but facilitates virion packaging and subsequent release (Johri et al, 2020). In addition, adjuvant treatment with sirolimus in combination with corticosteroids revealed better clinical outcomes in patients with influenza A virus subtype H1N1 mediated severe pneumonia and acute respiratory failure (Wang et al, 2014).…”

“…Valinomycin, a cyclodepsipeptide antibiotic that selectively induces the transport of potassium ion (K + ) across the membrane, and to date, the function of valinomycin has been elucidated in Parkin−/PINK1 regulated mitophagy (Narendra et al, 2010;Rakovic et al, 2019;Su et al, 2019).…”

Valinomycin as a potential antiviral agent against coronaviruses: A review

“…[ 82 ], the cardiac glycosides were identified as inhibitors of the membrane-bound Na + /K + -ATPase against the replication of RSV. Notably, VAL has a high selectivity for intracellular K + relative to Na + [ 47 ]. This mechanism of action of VAL on RSV at this stage of the replication cycle is the same as that of poliovirus.…”

“…The structure of VAL was determined as 12 stereogenic centers consisting of a three repeating sequence of the tetramer d -α-hydroxyisovaleric acid- d -valine- l -lactate- l -valine ( D -Hiv- D -Val- L -Lac- L -Val). VAL can selectively transport K + across model lipid bilayer membranes [ 47 ]. Furthermore, VAL is also a respiratory chain ionophore inhibitor that inhibits oxidative phosphorylation by increasing the permeability of the mitochondrial inner membrane to K + [ 48 ].…”

Polymorphic Forms of Valinomycin Investigated by NMR Crystallography

“…Their description furthers the understanding of the polymorphism of VLM (the ability of a solid VLM to form various crystal modifications). The polymorphism of VLM is expected to be extensive (see the recent study of a related problem of complexation-induced structural changes in VLM [ 9 ], and references cited therein) and important for the design and manufacturing of a drug formulation. Due to a great significance of the polymorphism for pharmaceutical industry, there is a number of methods dealing with various aspects of this problem [ 10 ].…”