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Drug Des Devel Ther
2018 Apr 30;12:1019-1031. doi: 10.2147/DDDT.S157104.
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Symmetric dimeric adamantanes for exploring the structure of two viroporins: influenza virus M2 and hepatitis C virus p7.
Mandour YM
,
Breitinger U
,
Ma C
,
Wang J
,
Boeckler FM
,
Breitinger HG
,
Zlotos DP
.
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Background: Adamantane-based compounds have been identified to interfere with the ion-channel activity of viroporins and thereby inhibit viral infection. To better understand the difference in the inhibition mechanism of viroporins, we synthesized symmetric dimeric adamantane analogs of various alkyl-spacer lengths.
Methods: Symmetric dimeric adamantane derivatives were synthesized where two amantadine or rimantadine molecules were linked by various alkyl-spacers. The inhibitory activity of the compounds was studied on two viroporins: the influenza virus M2 protein, expressed in Xenopus oocytes, using the two-electrode voltage-clamp technique, and the hepatitis C virus (HCV) p7 channels for five different genotypes (1a, 1b, 2a, 3a, and 4a) expressed in HEK293 cells using whole-cell patch-clamp recording techniques.
Results: Upon testing on M2 protein, dimeric compounds showed significantly lower inhibitory activity relative to the monomeric amantadine. The lack of channel blockage of the dimeric amantadine and rimantadine analogs against M2 wild type and M2-S31N mutant was consistent with previously proposed drug-binding mechanisms and further confirmed that the pore-binding model is the pharmacologically relevant drug-binding model. On the other hand, these dimers showed similar potency to their respective monomeric analogs when tested on p7 protein in HCV genotypes 1a, 1b, and 4a while being 700-fold and 150-fold more potent than amantadine in genotypes 2a and 3a, respectively. An amino group appears to be important for inhibiting the ion-channel activity of p7 protein in genotype 2a, while its importance was minimal in all other genotypes.
Conclusion: Symmetric dimeric adamantanes can be considered a prospective class of p7 inhibitors that are able to address the differences in adamantane sensitivity among the various genotypes of HCV.
Figure 1. Synthetic scheme for the preparation of compounds 2a–e.Notes: Reaction conditions: (A) oxalyl chloride, catalytic dimethylformamide, CHCl3, 4 hours; (B) amantadine, triethylamine, CHCl3, 16 hours; (C) 1 M borane–tetrahydrofuran complex, reflux 9 hours.
Figure 2. Synthetic scheme for the preparation of compounds 4a–e.Notes: Reaction conditions: (A) HO2C-(CH2)n-CO2H, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl, hydroxybenzotriazole, diisopropylethylamine in THF, 16 hours; (B) butyric acid, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide HCl, hydroxybenzotriazole, diisopropylethylamine in THF, 16 hours; (C, D) borane–THF complex in dry THF, reflux 9 hours.Abbreviation: THF, tetrahydrofuran.
Figure 3. M2-inhibitory activities of dimeric adamantanes.Notes: Evaluation of inhibitory activity of dimeric adamantane compounds on wild-type (A) and S31N mutant (B) M2 proteins. M2 protein was expressed in Xenopus oocytes and the compounds’ inhibitory activity measured using the two-electrode voltage-clamp technique at 100 µM concentration.
Figure 4. Inhibition of the influenza M2 proton channel.Notes: (A) Structure of amantadine (gray) in complex with M2 wild-type protein, as determined by solid-state nuclear magnetic resonance (Protein Data Bank [PDB] 2KQT),31 with the water molecules seen in the high-resolution crystallographic structure (PDB 3LBW)30 superimposed (red spheres). (B) Inhibition of amantadine-resistant M2-S31N protein by an isoxazole drug (PDB 2LY0).36 The adamantane cage is shifted downward in the structure of the S31N-mutant form, due to the constricted pore size.
Figure 5. J6 p7 hexameric structure model 1 (A) and model 2 (B).Notes: Overlay of the docked poses of amantadine (gray) and compound 2a (magenta). Side-chain atoms of Leu20 are shown as sticks. (C) Sequence alignment of p7 protein in GT5a and the five GTs under study – 1a, 1b, 2a, 3a, and 4a – showing the position of Pro49 indicated by the red arrow.Abbreviation: GT, genotype.
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