Cyclodepsipeptides: A Rich Source of Biologically Active Compounds for Drug Research

Faced with the need to find new drugs for all kinds of diseases, science sees that Nature offers numerous classes of compounds showing an impressively high biological potential. Among those are the cyclodepsipeptides, hybrid structures composed of amino and hydroxy acids. In the past decades numerous cyclodepsipeptides have been isolated and their potential as drugs has been studied extensively. For several cyclodepsipeptides total syntheses both in solution and on solid-phase have been established, allowing the production of combinatorial libraries. In addition, the biosynthesis of specific cyclodepsipeptides has been elucidated and used for the chemoenzymatic preparation of nonnatural analogues. This review summarizes the recent literature on cyclic tetra- to decadepsipeptides, composed exclusively of α-amino- and α-hydroxy acids

Elucidation of the solution conformations of loloatin C by NMR Spectroscopy and molecular simulation

NMR experiments combined with molecular simulation with X-PLOR have been employed to determine the solution conformation of the cyclic decapeptide loloatin C in three different solutions. In DMSO, the molecule possesses a hydrophobic aromatic "wall" consisting of Trp(6) and Phe(7), and a type I beta-turn structure involving Val(1), Trp(10), Asp(9) and Asn(8) with a hydrophobic head at Val(1)/Trp(10) and a hydrophilic tail at Asp(9) and Asn(8); another type II' P-turn was also located between Leu(3), Tyr(4), Pro(5), and Trp(6). In 70/30 [D-3]TFE/H2O, however, loloatin C possesses a dumbbell structure with all the hydrophobic side chains projecting upward on one side, forming a hydrophobic surface, and the hydrophilic side chains projecting to the other side, together with most of carbonyl oxygen atoms, thereby forming a hydrophilic surface. However, in 30:70 [D-3]TFE/H2O, loloatin C possesses an inverse gamma-turn incorporating Tyr(4), Pro(5), and Trp(6), a hydrophobic zone involving the side chains of Leu(3), Trp(6), Trp(10), and Phe(7) and a hydrophilic tail involving the hydrophilic side chains of Orn(2), Asn(8), and Asp(9). The amphiphilicity of the dumbbell structure in 70/30 [D-3]TFE/H2O is of interest in relation to the antibiotic activity of loloatin C. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Allosteric Activation of GDP-Bound Ras Isoforms by Bisphenol Derivative Plasticisers

The protein family of small GTPases controls cellular processes by acting as a binary switch between an active and an inactive state. The most prominent family members are H-Ras, N-Ras, and K-Ras isoforms, which are highly related and frequently mutated in cancer. Bisphenols are widespread in modern life because of their industrial application as plasticisers. Bisphenol A (BPA) is the best-known member and has gained significant scientific as well as public attention as an endocrine disrupting chemical, a fact that eventually led to its replacement. However, compounds used to replace BPA still contain the molecular scaffold of bisphenols. BPA, BPAF, BPB, BPE, BPF, and an amine-substituted BPAF-derivate all interact with all GDP-bound Ras-Isoforms through binding to a common site on these proteins. NMR-, SOScat-, and GDI- assay-based data revealed a new bisphenol-induced, allosterically activated GDP-bound Ras conformation that define these plasticisers as Ras allosteric agonists

The Natural Plant Product Rottlerin Activates Kv7.1/KCNE1 Channels

Background/Aims: Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 K+ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. Methods: Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in Xenopus laevis oocytes and on iPSC cardiomyocytes overexpressing Kv7.1 channels. Results: We show that currents carried by Kv7.1 (EC50 = 1.48 μM), Kv7.1/KCNE1 (EC50 = 4.9 μM), and Kv7.4 (EC50 = 0.148 μM) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1.Conclusion: Rottlerin or an optimized derivative holds a potential as QT interval correcting drug

Allosteric activation of GDP-bound ras isoforms by bisphenol derivative plasticisers

The protein family of small GTPases controls cellular processes by acting as a binary switch between an active and an inactive state. The most prominent family members are H-Ras, N-Ras, and K-Ras isoforms, which are highly related and frequently mutated in cancer. Bisphenols are widespread in modern life because of their industrial application as plasticisers. Bisphenol A (BPA) is the best-known member and has gained significant scientific as well as public attention as an endocrine disrupting chemical, a fact that eventually led to its replacement. However, compounds used to replace BPA still contain the molecular scaffold of bisphenols. BPA, BPAF, BPB, BPE, BPF, and an amine-substituted BPAF-derivate all interact with all GDP-bound Ras-Isoforms through binding to a common site on these proteins. NMR-, $SOS^{cat_{-}}$, and GDI- assay-based data revealed a new bisphenol-induced, allosterically activated GDP-bound Ras conformation that define these plasticisers as Ras allosteric agonists

Structural insights into antibacterial payload release from gold nanoparticles bound to E. coli\textit {E. coli} peptide deformylase

The lack of new antibiotics and the rapidly rising number of pathogens resistant to antibiotics pose a serious problem to mankind. In bacteria, the cell membrane provides the first line of defence to antibiotics by preventing them from reaching their molecular target. To overcome this entrance barrier, it has been suggested$^{[1]}$ that small Gold-Nanoparticles (AuNP) could possibly function as drug delivery systems for antibiotic ligands. Using actinonin-based ligands, we provide here proof-of-principle of AuNP functionalisation, the capability to bind and inhibit the target protein of the ligand, and the possibility to selectively release the antimicrobial payload. To this end, we successfully synthesised AuNP coated with thio-functionalised actinonin and a derivative. Interactions between $^{15}$N-enriched His-peptide deformylase 1–147 from $\textit {E. coli}$ (His-ecPDF 1–147) and compound-coated AuNP were investigated $\it via$ 2D $^{1}H-^{15}$N-HSQC NMR spectra proving the direct binding to His-ecPDF 1–147. More importantly by adding dithiothreitol (DTT), we show that the derivative is successfully released from AuNPs while still bound to His-ecPDF 1–147. Our findings indicate that AuNP-conjugated ligands can address and bind intracellular target proteins. The system introduced here presents a new delivery platform for antibiotics and allows for the easy optimisation of ligand coated AuNPs

The natural plant product Rottlerin activates Kv7.1/KCNE1 channels

$\textit {Background/Aims:}$ Acquired as well as inherited channelopathies are disorders that are caused by altered ion channel function. A family of channels whose malfunction is associated with different channelopathies is the Kv7 $K^{+}$ channel family; and restoration of normal Kv7 channel function by small molecule modulators is a promising approach for treatment of these often fatal diseases. $\textit {Methods:}$ Here, we show the modulation of Kv7 channels by the natural compound Rottlerin heterologously expressed in $\textit {Xenopus laevisoocytes}$ and on iPSC cardiomyocytes overexpressing Kv7.1 channels. $\textit {Results:}$ We show that currents carried by Kv7.1 ($EC_{50}$ = 1.48 $\mu$M), Kv7.1/KCNE1 ($EC_{50}$ = 4.9 $\mu$M), and Kv7.4 ($EC_{50}$ = 0.148 $\mu$M) are strongly enhanced by the compound, whereas Kv7.2, Kv7.2/Kv7.3, and Kv7.5 are not sensitive to Rottlerin. Studies on Kv7.1/KCNE1 mutants and in silico modelling indicate that Rottlerin binds to the R-L3-activator site. Rottlerin mediated activation of Kv7.1/KCNE1 channels might be a promising approach in long QT syndrome. As a proof of concept, we show that Rottlerin shortens cardiac repolarisation in iPSC-derived cardiomyocytes expressing Kv7.1. $\textit {Conclusion:}$ Rottlerin or an optimized derivative holds a potential as QT interval correcting drug