Search

Toft-Bertelsen et al. describe repurposing of anti-influenza drug amantadine and its derivatives for the treatment of SARS-CoV-2. They show that Amantadine, Emodin and Xanthene show significant blockage of ionchannels formed by SARS-CoV-2 which are crucial for its assembly and pathophysiology.

We present here an improved procedure for the preparation of the promising antitubercular drug SQ109 that is currently in phase Ib/III of clinical trials against Mycobacterium tuberculosis. We investigated and tested the literature synthetic procedure that enables the development of structure–activity relationships and report the observed inconsistencies as well as presenting improvements or novelties for the more efficient preparation of SQ109. Most significantly we applied a novel reduction step of the aminoamide precursor using Me3SiCl­/LiAlH4 under mild conditions. These findings are important for research groups investigating the efficacy of this drug and analogues in academia and industry.

Influenza A viruses can cause a serious future threat due to frequent mutations. Amantadine and rimantadine drugs inhibit influenza A M2 wild-type (WT; bearing in the protein M2 proton channel serine at position-31) viruses by binding and blocking M2 WT channel-mediated proton current. The resistant to these drugs influenza A viruses bearing the S31N mutant in the M2 proton channel can be inhibited by amantadine – aryl conjugates, in which amantadine and an aryl group are linked through a methylene, which block M2 S31N channel-mediated proton current. However, the M2 amantadine/rimantadine resistant viruses bearing one of the four mutations L26F, V27A, A30T, G34E in residues that line the M2 channel pore pose an additional concern for public health.Here, we designed 33 compounds based on the structure of three previously published and potent amantadine-aryl conjugates against M2 S31N virus, by replacing amantadine with 16 amantadine variants. The compounds were tested against M2 WT and the five M2 amantadine resistant viruses aiming at identifying inhibitors against multiple M2 mutant – amantadine resistant viruses.We identified 16 compounds that inhibited in vitro two influenza A viruses with M2 WT or L26F channels. Additionally, compounds 21 or 32 or 33, which are conjugates of the rimantadine variant with CMe2 (instead of CHMe in rimantadine) or the diamantylamine or the 4-(1-adamantyl)benzenamine with the 2-hydroxy-4-methoxyphenyl aryl group, were in vitro inhibitors against three influenza A viruses with M2 WT or L26F or S31N, while compound 21 inhibited also in vitro the M2 G34E virus and compound 32 inhibited also in vitro the M2 A30T virus. Also, using electrophysiology, we showed that compound 21 was an efficient blocker of the M2 WT and M2 L26F channels, compound 32 blocked efficiently the M2 WT channel and compound 33 blocked the M2 WT, L26F and V27A channels. The drug metabolism and pharmacokinetics studies showed that these compounds need further optimization.

G protein-coupled receptors (GPCRs) are embedded in phospholipid membrane bilayers with cholesterol representing 34% of the total lipid content in mammalian plasma membranes. Membrane lipids interact with GPCRs structures and modulate their function and drug-stimulated signaling through conformational selection. It has been shown that anionic phospholipids form strong interactions between positively charged residues in the G protein and the TM5-TM6-TM 7 cytoplasmic interface of class A GPCRs stabilizing the signaling GPCR-G complex. Cholesterol with a high content in plasma membranes can be identified in more specific sites in the transmembrane region of GPCRs, such as the Cholesterol Consensus Motif (CCM) and Cholesterol Recognition Amino Acid Consensus (CRAC) motifs and other receptor dependent and receptor state dependent sites. Experimental biophysical methods, atomistic (AA) MD simulations and coarse-grained (CG) molecular dynamics simulations have been applied to investigate these interactions. We emphasized here the impact of phosphatidyl inositol-4,5-bisphosphate (PtdIns(4,5)P2 or PIP2), a minor phospholipid component and of cholesterol on the function-related conformational equilibria of the human A2A adenosine receptor (A2AR), a representative receptor in class A GPCR. Several GPCRs of class A interacted with PIP2 and cholesterol and in many cases the mechanism of the modulation of their function remains unknown. This review provides a helpful comprehensive overview for biophysics that enter the field of GPCRs-lipid systems.

We present an overview of fundamental catalytic reactions of nucleophiles with π-systems in relation to gold chemistry. We present examples of reactions with gold-activated π-systems, alkynyl or allenyl moieties, and the regulation of their reactivity due to the presence of an electron-donating or -withdrawing group. The reactions describe furnished hard-to-reach heterocyclic building blocks for medicinal chemistry purposes. Important gold(I) or gold(III) complexes that are used as catalysts are presented. We examine the activation of such π-systems using gold(I) or gold(III) catalysts and the corresponding divergent catalytic transformations. We provide examples of divergent catalysis using gold(I) catalyst and other metal catalysts (Pt, Ag, Pd, Rh, Sc, Cu) or by changing the ligands in gold(I) catalyst complexes. We also discuss the role of the solvent, counterions and additives in gold(I)-catalyzed reactions. We mention, in a few cases, characteristic experimental or computational studies of these gold-catalyzed reactions of nucleophiles with π-systems.

α-Imino gold carbenoid species have been recognized as key intermediates in a plethora of processes involving gold-activated alkynes. Here, we explored the pathways of the Au(I)-catalyzed [3 + 2] reaction between the mild nucleophiles: anthranil, 1,2,4-oxadiazole, or 4,5-dihydro-1,2,4-oxadiazole, and an ynamide, PhC≡C-N(Ts)Me, proceeding via the formation of the aforementioned α-imino gold carbene intermediate which, after intramolecular capture, regioselectively produces 2-amino-3-phenyl-7-acyl indoles, N-acyl-5-aminoimidazoles, or N-alkyl-4-aminoimidazoles, respectively. In all cases, the regioselectivity of the substituents at 2, 3 in the 7-acyl-indole ring and 4, 5 in the substituted imidazole ring is decided at the first transition state, involving the attack of nitrogen on the C1 or C2 carbon of the activated ynamide. A subsequent and steep energy drop furnishes the key α-imino gold carbene. These features are more pronounced for anthranil and 4,5-dihydro-1,2,4-oxadiazole reactions. Strikingly, in the 4,5-dihydro-1,2,4-oxadiazole reaction the significant drop of energy is due to the formation of an unstable α-imino gold carbene, which after a spontaneous benzaldehyde elimination is converted to a stabilized one. Compared to anthranil, the reaction pathways for 1,2,4-oxadiazoles or 4,5-dihydro-1,2,4-oxadiazoles are found to be significantly more complex than anticipated in the original research. For instance, compared to the formation of a five-member ring from the α-imino gold carbene, one competitive route involves the formation of intermediates consisting of a four-member ring condensed with a three-member ring, which after a metathesis and ring expansion led to the imidazole ring.

Multimeric ligands consisting of multiple pharmacophores connected to a single backbone have been widely investigated for diagnostic and therapeutic applications. In this review, we summarize recent developments regarding multimeric radioligands targeting integrin αvβ3 receptors on cancer cells for molecular imaging and diagnostic applications using positron emission tomography (PET). Integrin αvβ3 receptors are glycoproteins expressed on the cell surface, which have a significant role in tumor angiogenesis. They act as receptors for several extracellular matrix proteins exposing the tripeptide sequence arginine-glycine-aspartic (RGD). Cyclic RDG peptidic ligands c(RGD) have been developed for integrin αvβ3 tumor-targeting positron emission tomography (PET) diagnosis. Several c(RGD) pharmacophores, connected with the linker and conjugated to a chelator or precursor for radiolabeling with different PET radionuclides (18F, 64Cu, and 68Ga), have resulted in multimeric ligands superior to c(RGD) monomers. The binding avidity, pharmacodynamic, and PET imaging properties of these multimeric c(RGD) radioligands, in relation to their structural characteristics are analyzed and discussed. Furthermore, specific examples from preclinical studies and clinical investigations are included.

G protein-coupled receptors (GPCRs) are embedded in phospholipid membrane bilayers with cholesterol representing 34% of the total lipid content in mammalian plasma membranes. Membrane lipids interact with GPCRs structures and modulate their function and drug-stimulated signaling through conformational selection. It has been shown that anionic phospholipids form strong interactions between positively charged residues in the G protein and the TM5-TM6-TM 7 cytoplasmic interface of class A GPCRs stabilizing the signaling GPCR-G complex. Cholesterol with a high content in plasma membranes can be identified in more specific sites in the transmembrane region of GPCRs, such as the Cholesterol Consensus Motif (CCM) and Cholesterol Recognition Amino Acid Consensus (CRAC) motifs and other receptor dependent and receptor state dependent sites. Experimental biophysical methods, atomistic (AA) MD simulations and coarse-grained (CG) molecular dynamics simulations have been applied to investigate these interactions. We emphasized here the impact of phosphatidyl inositol-4,5-bisphosphate (PtdIns(4,5)P2 or PIP2), a minor phospholipid component and of cholesterol on the function-related conformational equilibria of the human A2A adenosine receptor (A2AR), a representative receptor in class A GPCR. Several GPCRs of class A interacted with PIP2 and cholesterol and in many cases the mechanism of the modulation of their function remains unknown. This review provides a helpful comprehensive overview for biophysics that enter the field of GPCRs-lipid systems. [ABSTRACT FROM AUTHOR]

We present an overview of fundamental catalytic reactions of nucleophiles with π-systems in relation to gold chemistry. We present examples of reactions with gold-activated π-systems, alkynyl or allenyl moieties, and the regulation of their reactivity due to the presence of an electron-donating or -withdrawing group. The reactions describe furnished hard-to-reach heterocyclic building blocks for medicinal chemistry purposes. Important gold(I) or gold(III) complexes that are used as catalysts are presented. We examine the activation of such π-systems using gold(I) or gold(III) catalysts and the corresponding divergent catalytic transformations. We provide examples of divergent catalysis using gold(I) catalyst and other metal catalysts (Pt, Ag, Pd, Rh, Sc, Cu) or by changing the ligands in gold(I) catalyst complexes. We also discuss the role of the solvent, counterions and additives in gold(I)-catalyzed reactions. We mention, in a few cases, characteristic experimental or computational studies of these gold-catalyzed reactions of nucleophiles with π-systems. [ABSTRACT FROM AUTHOR]

Here, we have carried out a proof-of-concept molecular dynamics (MD) simulation with adaptive tempering in a membrane mimetic environment to study the folding of single-pass membrane peptides. We tested the influenza A M2 viroporin, influenza B M2 viroporin, and protein E from coronaviruses MERS-Cov-2 and SARS-CoV-2 peptides with known experimental secondary structures in membrane bilayers. The two influenza-derived peptides are significantly different in the peptide sequence and secondary structure and more polar than the two coronavirus-derived peptides. Through a total of more than 50 μs of simulation time that could be accomplished in trifluoroethanol (TFE), as a membrane model, we characterized comparatively the folding behavior, helical stability, and helical propensity of these transmembrane peptides that match perfectly their experimental secondary structures, and we identified common motifs that reflect their quaternary organization and known (or not) biochemical function. We showed that BM2 is organized into two structurally distinct parts: a significantly more stable N-terminal half, and a fast-converting C-terminal half that continuously folds and unfolds between α-helical structures and non-canonical structures, which are mostly turns. In AM2, both the N-terminal half and C-terminal half are very flexible. In contrast, the two coronavirus-derived transmembrane peptides are much more stable and fast helix-formers when compared with the influenza ones. In particular, the SARS-derived peptide E appears to be the fastest and most stable helix-former of all the four viral peptides studied, with a helical structure that persists almost without disruption for the whole of its 10 μs simulation. By comparing the results with experimental observations, we benchmarked TFE in studying the conformation of membrane and hydrophobic peptides. This work provided accurate results suggesting a methodology to run long MD simulations and predict structural properties of biologically important membrane peptides. [ABSTRACT FROM AUTHOR]

Indole is a very common structural motif in alkaloids with a remarkable history in pharma industry. In the continuous search for more direct and efficient access to these valuable structures, a new and rather elegant approach was found by Jin and coworkers, which involved a gold(I)‐mediated addition of alkynes onto anthralins. This approach selectively furnishes 7‐acylindoles in a rather expeditious way, and it has been shown to be compatible with a large range of decorated reactants, both at the alkyne side and at the anthralin side. We studied the mechanism of this reaction with a set of different alkynes, including disubstituted ones, to establish similarities and differences between them and to aid in the elucidation of key steps in the reaction pathway. The observed regioselectivity seems to be connected to the irreversible formation of a key α‐imino gold carbene intermediate, common to all reaction profiles, through the initial regioselective nucleophilic attack of the anthranil N atom onto the alkyne fragment. [ABSTRACT FROM AUTHOR]

α-Imino gold carbenoid species have been recognized as key intermediates in a plethora of processes involving gold-activated alkynes. Here, we explored the pathways of the Au(I)-catalyzed [3 + 2] reaction between the mild nucleophiles: anthranil, 1,2,4-oxadiazole, or 4,5-dihydro-1,2,4-oxadiazole, and an ynamide, PhC≡C-N(Ts)Me, proceeding via the formation of the aforementioned α-imino gold carbene intermediate which, after intramolecular capture, regioselectively produces 2-amino-3-phenyl-7-acyl indoles, N-acyl-5-aminoimidazoles, or N-alkyl-4-aminoimidazoles, respectively. In all cases, the regioselectivity of the substituents at 2, 3 in the 7-acyl-indole ring and 4, 5 in the substituted imidazole ring is decided at the first transition state, involving the attack of nitrogen on the C1 or C2 carbon of the activated ynamide. A subsequent and steep energy drop furnishes the key α-imino gold carbene. These features are more pronounced for anthranil and 4,5-dihydro-1,2,4-oxadiazole reactions. Strikingly, in the 4,5-dihydro-1,2,4-oxadiazole reaction the significant drop of energy is due to the formation of an unstable α-imino gold carbene, which after a spontaneous benzaldehyde elimination is converted to a stabilized one. Compared to anthranil, the reaction pathways for 1,2,4-oxadiazoles or 4,5-dihydro-1,2,4-oxadiazoles are found to be significantly more complex than anticipated in the original research. For instance, compared to the formation of a five-member ring from the α-imino gold carbene, one competitive route involves the formation of intermediates consisting of a four-member ring condensed with a three-member ring, which after a metathesis and ring expansion led to the imidazole ring. [ABSTRACT FROM AUTHOR]

Research has been conducted on the equatorial adamantyl and axial methyl groups. Results indicate that the chair conformation with these groups is the most stable and that the interactions between the groups is conformation-determining.

The dire need for COVID-19 treatments has inspired strategies of repurposing approved drugs. Amantadine has been suggested as a candidate, and cellular as well as clinical studies have indicated beneficial effects of this drug. We demonstrate that amantadine and hexamethylene-amiloride (HMA), but not rimantadine, block the ion channel activity of Protein E from SARS-CoV-2, a conserved viroporin among coronaviruses. These findings agree with their binding to Protein E as evaluated by solution NMR and molecular dynamics simulations. Moreover, we identify two novel viroporins of SARS-CoV-2; ORF7b and ORF10, by showing ion channel activity in a X. laevis oocyte expression system. Notably, amantadine also blocks the ion channel activity of ORF10, thereby providing two ion channel targets in SARS-CoV-2 for amantadine treatment in COVID-19 patients. A screen of known viroporin inhibitors on Protein E, ORF7b, ORF10 and Protein 3a from SARS-CoV-2 revealed inhibition of Protein E and ORF7b by emodin and xanthene, the latter also blocking Protein 3a. This illustrates a general potential of well-known ion channel blockers against SARS-CoV-2 and specifically a dual molecular basis for the promising effects of amantadine in COVID-19 treatment. We therefore propose amantadine as a novel, cheap, readily available and effective way to treat COVID-19. Toft-Bertelsen et al. describe repurposing of anti-influenza drug amantadine and its derivatives for the treatment of SARS-CoV-2. They show that Amantadine, Emodin and Xanthene show significant blockage of ionchannels formed by SARS-CoV-2 which are crucial for its assembly and pathophysiology. [ABSTRACT FROM AUTHOR]

The correct balance between attractive, repulsive and peptide hydrogen bonding interactions must be attained for proteins to fold correctly. To investigate these important contributors, we sought a comparison of the folding between two 25‐residues peptides, the influenza A M2 protein transmembrane domain (M2TM) and the 25‐Ala (Ala25). M2TM forms a stable α‐helix as is shown by circular dichroism (CD) experiments. Molecular dynamics (MD) simulations with adaptive tempering show that M2TM monomer is more dynamic in nature and quickly interconverts between an ensemble of various α‐helical structures, and less frequently turns and coils, compared to one α‐helix for Ala25. DFT calculations suggest that folding from the extended structure to the α‐helical structure is favored for M2TM compared with Ala25. This is due to CH⋯O attractive interactions which favor folding to the M2TM α‐helix, and cannot be described accurately with a force field. Using natural bond orbital (NBO) analysis and quantum theory atoms in molecules (QTAIM) calculations, 26 CH⋯O interactions and 22 NH⋯O hydrogen bonds are calculated for M2TM. The calculations show that CH⋯O hydrogen bonds, although individually weaker, have a cumulative effect that cannot be ignored and may contribute as much as half of the total hydrogen bonding energy, when compared to NH⋯O, to the stabilization of the α‐helix in M2TM. Further, a strengthening of NH⋯O hydrogen bonding interactions is calculated for M2TM compared to Ala25. Additionally, these weak CH⋯O interactions can dissociate and associate easily leading to the ensemble of folded structures for M2TM observed in folding MD simulations. [ABSTRACT FROM AUTHOR]