The Location of the Protonated and Unprotonated Forms of Arbidol in the Membrane: A Molecular Dynamics Study

Abstract

Arbidol is a potent broad-spectrum antiviral molecule for the treatment and prophylaxis of many viral infections. Viruses that can be inhibited by arbidol include enveloped and non-enveloped viruses, RNA and DNA viruses, as well as pH-independent and pH-dependent ones. These differences in viral types highlight the broad spectrum of Arb antiviral activity and, therefore, it must affect a common viral critical step. Arbidol incorporates rapidly into biological membranes, and some of its antiviral effects might be related to its capacity to interact with and locate into the membrane. However, no information is available of the molecular basis of its antiviral mechanism/s. We have aimed to locate the protonated (Arp) and unprotonated (Arb) forms of arbidol in a model membrane system. Both Arb and Arp locate in between the hydrocarbon acyl chains of the phospholipids but its specific location and molecular interactions differ from each other. Whereas both Arb and Arp average location in the membrane palisade is a similar one, Arb tends to be perpendicular to the membrane surface, whereas Arp tends to be parallel to it. Furthermore, Arp, in contrast to Arb, seems to interact stronger with POPG than with POPC, implying the existence of a specific interaction between Arp, the protonated from, with negatively charged phospholipids. This data would suggest that the active molecule of arbidol in the membrane is the protonated one, i.e., the positively charged molecule. The broad antiviral activity of arbidol would be defined by the perturbation it exerts on membrane structure and therefore membrane functioning.

SARS-CoV-2 Protein S Fusion Peptide Is Capable of Wrapping Negatively-Charged Phospholipids

“…The model late endosomal membrane systems contained 68/69 molecules of POPC, 30 molecules of POPE, 8 molecules of POPS, 12 of PI-3P, 12 molecules of PSM, 23 molecules of BMGP and 36/37 of cholesterol (CHOL) [ 33 , 45 , 46 ] ( Supplementary Table S3 ). Each one of the systems was composed of one molecule of FP, membrane bilayer, water, and NaCl at physiological conditions, i.e., a concentration of 0.15 M, enclosed in a rectangular box and a neutral setting ( Supplementary Table S3 ) [ 47 , 48 , 49 ]. The FP peptide pertained to the averaged and minimized fifteen NMR structures (PDB code 7MY8 [ 19 ], see above).…”

Procyanidin C1 Location, Interaction, and Aggregation in Two Complex Biomembranes

“…The systems contained excess water [ 40 ]. Each one of the systems was composed of PC1 molecules, a membrane bilayer, water, and NaCl at physiological conditions, i.e., a concentration of 0.15 M, enclosed in a rectangular box, and in a neutral setting ( Table 1 ) [ 41 , 42 , 43 ]. The PM system contained 80 molecules of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 48 molecules of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoethanolamine (POPE), 18 molecules of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoserine (POPS), 16 molecules of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoinositol-3-phosphate (PI-3P), 34 molecules of N-stearoyl-D-erythro-sphingosylphosphorylcholine (PSM), and 84 molecules of cholesterol (CHOL).…”

Arbidol: The current demand, strategies, and antiviral mechanisms

“…ARB is a weak alkaline drug that can increase the pH of the intracellular environment, making the virus unable to complete the process of membrane fusion and release the virus genome, resulting in effective inhibition of virus infection. 74 Moreover, ARB directly interacts with all virus HA subtypes, among which H7 has the strongest affinity; ARB dwells in a discrete binding capsule, 75 forming an ARB-HA complex and enhancing the structural stability of HA, inhibiting the pH-induced transition of HA into its functional fusogenic state, resulting in failure of membrane fusion. 64,67,76,77 3.1.2 | ARB inhibits virus replication ARB can inhibit influenza virus replication; enveloped RNA viruses are more sensitive to ARB than nonenveloped DNA viruses.…”

“…An acidic environment (pH 5.0) is needed for the membrane fusion of the influenza virus and host cells, and changes in pH will hinder the fusion process. ARB is a weak alkaline drug that can increase the pH of the intracellular environment, making the virus unable to complete the process of membrane fusion and release the virus genome, resulting in effective inhibition of virus infection 74 . Moreover, ARB directly interacts with all virus HA subtypes, among which H7 has the strongest affinity; ARB dwells in a discrete binding capsule, 75 forming an ARB‐HA complex and enhancing the structural stability of HA, inhibiting the pH‐induced transition of HA into its functional fusogenic state, resulting in failure of membrane fusion 64,67,76,77 …”