5-membered cyclic hydroxamic acids as HDAC inhibitors.

The new histone deacylases inhibitors (HDACi) were synthesized in the class of 5-membered cyclic hydroxamic acids (5-CHA), showing medium size CHA as a new Zn-binding group. New reaction sequence was proposed for the synthesis of 5-membered alkylidene-cyclic-hydroxamic acids starting from butyrolactone. Compound 10c showed low µM activity on HeLa cell extracts.

Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit.

Antimalarial hit 1 SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1 SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues.

Libiguins A and B: novel phragmalin limonoids isolated from Neobeguea mahafalensis causing profound enhancement of sexual activity.

In a screening programme directed towards the discovery of drugs that could enhance sexual activity, we found that a decoction of the root bark of Neobeguea mahafalensis displayed an extraordinarily high potency and remarkably long duration in augmenting sexual activity in male rodents. Bioassay-guided fractionation led to the isolation of two pharmacoactive constituents, which turned out to be novel 1,8,9-orthoacetate phragmalin limonoids that we named libiguins A and B, each with a C-16/30 δ-lactone ring. Chemical structures were established by the interpretation of their 1D and 2D NMR data.

Oligomerization of indole derivatives with incorporation of thiols.

Two molecules of indole derivative, e.g. indole-5-carboxylic acid, reacted with one molecule of thiol, e.

Design and synthesis of a library of tertiary amides: evaluation as mimetics of the melanocortins' active core.

Two hundred and ten tertiary amides were prepared on solid phase. Diamines were coupled to activated carboxylated Wang polymer, and the polymeric substituted benzyloxycarbonyl protected diamines obtained were reacted with aldehydes or ketones in trimethyl orthoformate giving resin attached Schiff bases. Coupled resins were then reduced to secondary amines by sodium cyanoborohydride in 4% acetic acid/trimethyl orthoformate, followed by acylation with the carboxylic acid in the presence of PyBroP and diisopropylethylamine.

Proteochemometric analysis of small cyclic peptides' interaction with wild-type and chimeric melanocortin receptors.

The melanocortin (MC) system confines unique G-protein coupled receptor pathways, which include the MC(1-5) receptors and their endogenous agonists and antagonists, the MCs and the agouti and agouti-related proteins. The MC4 receptor is an important target for development of drugs for treatment of obesity and cachexia. While natural MC peptides are selective for the MC1 receptor, some cyclic pentapeptides, such as the HS-129 peptide, show high selectivity for the MC4 receptor.

Proteochemometric modeling reveals the interaction site for Trp9 modified alpha-MSH peptides in melanocortin receptors.

The interactions of alpha-MSH peptides with melanocortin receptors (MCRs) were located by proteochemometric modeling. Nine alpha-MSH peptide analogues were constructed by exchanging the Trp9 residue in the alpha-MSH core with the natural or artificial amino acids Arg, Asp, Cys, Gly, Leu, Nal, d-Nal, Pro, or d-Trp. The nine peptides created, and alpha-MSH itself, were evaluated for their interactions with the 4 wild-type MC(1,3-5)Rs and 15 multichimeric MCRs, each of the latter being constructed from three sequence segments, each taken from a different wild-type MC(1,3-5)R.

A look inside HIV resistance through retroviral protease interaction maps.

Retroviruses affect a large number of species, from fish and birds to mammals and humans, with global socioeconomic negative impacts. Here the authors report and experimentally validate a novel approach for the analysis of the molecular networks that are involved in the recognition of substrates by retroviral proteases. Using multivariate analysis of the sequence-based physiochemical descriptions of 61 retroviral proteases comprising wild-type proteases, natural mutants, and drug-resistant forms of proteases from nine different viral species in relation to their ability to cleave 299 substrates, the authors mapped the physicochemical properties and cross-dependencies of the amino acids of the proteases and their substrates, which revealed a complex molecular interaction network of substrate recognition and cleavage.

Kinetic evidence for tandemly arranged ligand binding sites in melanocortin 4 receptor complexes.

The melanocortin 4 receptor (MC(4)R) binding of the peptide analogue of melanocyte stimulating hormone, [(125)I]NDP-MSH, and the low molecular weight radionucleid 1-(D-1,2,3,4-tetrahydroisoquinoline-3-carboxy-D-4-(125)iodophenylalanyl)-4-cyclohexyl-4-[(1,2,4-triazol-1-yl)methyl]piperidine trifluoroacetate ([(125)I]THIQ) were compared. Kinetic analysis indicated heterogeneity in the binding of both radioligands, the binding apparently proceeding to two tandemly arranged interconnected mutually dependent binding sites. Steric considerations and BRET analysis of Rluc and GFP tagged receptors proposed that these sites are located on different subunits of receptor dimers, which form receptor complexes.

Probing the substrate specificity of the dengue virus type 2 NS3 serine protease by using internally quenched fluorescent peptides.

The NS3 (dengue virus non-structural protein 3) serine protease of dengue virus is an essential component for virus maturation, thus representing an attractive target for the development of antiviral drugs directed at the inhibition of polyprotein processing. In the present study, we have investigated determinants of substrate specificity of the dengue virus NS3 protease by using internally quenched fluorogenic peptides containing Abz (o-aminobenzoic acid; synonymous to anthranilic acid) and 3-nitrotyrosine (nY) representing both native and chimaeric polyprotein cleavage site sequences. By using this combinatorial approach, we were able to describe the substrate preferences and determinants of specificity for the dengue virus NS2B(H)-NS3pro protease.

The MC3 receptor binding affinity of melanocortins correlates with the nitric oxide production inhibition in mice brain inflammation model.

Melanocortins possess strong anti-inflammatory effects acting in the central nervous system via inhibition of the production of nitric oxide (NO) during brain inflammation. To shed more light into the role of melanocortin (MC) receptor subtypes involved we synthesized and evaluated some novel peptides, modified in the melanocyte-stimulating hormone (MSH) core structure, natural MCs and known MC receptor selective peptides - MS05, MS06. Since the study included both selective, high affinity binders and the novel peptides, it was possible to do the correlation analysis of binding activities and the NO induction-related anti-inflammatory effect of the peptides.

N-alkylated dipeptide amides and related structures as imitations of the melanocortins' active core.

Thirty-three low molecular mass structures combining both peptide and peptoid features were prepared and tested on human melanocortin receptors MC1,3-5R. Most of them displayed low micromolar activity with preference for diamines, guanidino and 2-naphthyl derivatives compared to monoacetylated, amino and 3-indolyl counterparts. Some contained L- or D-histidine residues, but the change did not influence affinity.

Co-operative regulation of ligand binding to melanocortin receptor subtypes: evidence for interacting binding sites.

This study evaluates the binding the melanocyte stimulating hormone peptide analogue [125I]NDP-MSH to melanocortin receptors MC1, MC3, MC4 and MC5 in insect cell membranes produced by baculovirus expression systems. The presence of Ca2+ was found to be mandatory to achieve specific [125I]NDP-MSH binding to the melanocortin receptors. Although association kinetics of [125I]NDP-MSH followed the regularities of simple bimolecular reactions, the dissociation of [125I]NDP-MSH from the melanocortin receptors was heterogeneous.

Proteochemometric mapping of the interaction of organic compounds with melanocortin receptor subtypes.

Proteochemometrics was applied in the analysis of the binding of organic compounds to wild-type and chimeric melanocortin receptors. Thirteen chimeric melanocortin receptors were designed based on statistical molecular design; each chimera contained parts from three of the MC(1,3-5) receptors. The binding affinities of 18 compounds were determined for these chimeric melanocortin receptors and the four wild-type melanocortin receptors.

New substituted piperazines as ligands for melanocortin receptors. Correlation to the X-ray structure of "THIQ".

A series of piperazine analogues of the melanocortin 4 receptor (MC4R) specific small-molecule agonist "THIQ" was synthesized and characterized structurally and pharmacologically. First, several THIQ imitations lacking the triazole moiety were prepared. Syntheses included acylation of 4-phenylpiperazine or 4-cyclohexylpiperazine.

QSAR and proteo-chemometric analysis of the interaction of a series of organic compounds with melanocortin receptor subtypes.

We have created quantitative structure-activity relationship (QSAR) models describing the interaction of a series of 54 organic compounds with four melanocortin (MC) receptor subtypes, MC(1), MC(3), MC(4), and MC(5). In addition to traditional QSAR analysis, we applied our recently developed proteo-chemometrics approach. Proteo-chemometrics is based on the combined analysis of series of receptors and ligands, wherein descriptions of ligands, proteins, and so-called ligand-protein cross-terms are correlated with interaction activities.

Novel selective melanocortin 4 receptor antagonist induces food intake after peripheral administration.

We synthesized a new series of small cyclic melanocyte-stimulating hormone (MSH) analogues and screened them for binding affinity at the four MSH binding melanocortin (MC) receptors. We identified a novel substance HS131, with about 20-fold higher affinity for the MC4 receptor than the MC3 receptor. This substance proved to be antagonist for all the four MC receptors in a cAMP assay.

A simple and effective method for producing nonrandom peptide libraries using cotton as a carrier in continuous flow peptide synthesizers.

A method has been developed for generating nonrandom peptide libraries on cotton. Disks of cotton fabric were chemically modified to enable peptide synthesis. Incorporation of a 6-aminocaproic acid residue handle on the cellulose turned out to be advantageous.

Subtype selective binding properties of substituted linear melanocyte stimulating hormone analogues.

The melanocortin receptors are peptide binding G-protein coupled receptors that play a role in important physiological functions such as energy balance, inflammatory processes and several aspects of reproduction. In this study, we synthesised 11 new linear MSH analogues and tested their binding to the human MC receptors (MC1, MC3, MC4 and MC5) expressed in COS cells. Our results show that introduction of Asp in position 4 similarly affects the binding to the MC1, MC4 and MC5 receptors, but drastically lowers the binding to the MC3 receptor.

Design, synthesis and biological evaluation of cyclic angiotensin II analogues with 3,5 side-chain bridges. Role of C-terminal aromatic residue and ring cluster for activity and implications in the drug design of AT1 non-peptide antagonists.

The novel amide linked angiotensin II (ANG II) cyclic analogues: gamma, epsilon -cyclo(3, 5)-[Sar(1)-Glu(3)-Lys(5)-Ile(8)] ANG II (I) and gamma, epsilon -cyclo(3, 5)-[Sar(1)-Glu(3)-Lys(5)-Phe(8)] ANG II (II) have been designed, synthesized and bioassayed in anesthetized rabbits in order to unravel structural ring cluster characteristics important for receptor activation. Analogue I with Ile at position 8 was an inhibitor of Angiotensin II while analogue II with Phe at position 8 was found to be an agonist. Similar results were reported for cyclic compounds that have reversed the linking between positions 3 and 5.

N-alkylaminoacids and their derivatives interact with melanocortin receptors.

Thirty four N-alkylaminoacids (Arg, Trp, Nal, Pro, Hyp, L and D) and derivatives were prepared by a process that included reductive alkylation of the amino function. Both solid phase and solution synthesis was used. Title substances displayed binding activity on melanocortin receptors MC(1,3-5) reaching the low micromolar range.

Reductive amination products containing naphthalene and indole moieties bind to melanocortin receptors.

Presumed pharmacophoric groups of melanocortin peptides (naphthalene, amino or guanidine, and indole moieties) were combined in mimetics molecules looking for their favorable location for activity at melanocortin (MC) receptors. Twenty-two compounds were prepared and tested. The best of these displayed micromolar affinities for the MC receptors.