Productes naturals com a font de nous fàrmacs: Síntesi en fase sòlida de depsipèptids ciclics i aïllament d'agents antitumorals d'esponges marines

[cat] Els productes naturals són de gran importància en els sistemes de prevenció i de cura de les dolences i malalties de l'ésser humà. Així, un 50% dels fàrmacs actuals estan basats en productes naturals i un 80% de la població mundial depèn, encara avui, de la medicina tradicional. El procés de desenvolupament d'un nou fàrmac a partir d'un producte natural és llarg i complex. Les millores introduïdes recentment i de forma generalitzada a cadascuna de les etapes del procés han suposat una renovació de l'interès de la indústria farmacèutica per nous compostos naturals bioactius. La síntesi química té un paper rellevant en el procés de desenvolupament d'un nou fàrmac: la síntesi química del producte bioactiu permet assegurar la identitat del compost, així com assegurar la producció a gran escala per permetre la realització dels assaigs clínics i donar resposta a les demandes del mercat farmacèutic. La introducció de la química en fase sòlida ha estat una de les millores més importants en l'àrea de la síntesi química, permetent una exploració sintètica més ràpida i eficaç. Aquest canvi ha estat rellevant en la síntesi de pèptids i oligonucleòtids i, especialment determinant, en l'obtenció de depsipèptids cíclics produïts per microorganismes i d'interessant activitat i interès com a nous fàrmacs. Així, en la present tesi s'ha treballat en el desenvolupament de noves síntesis en fase sòlida de dos depsipèptids cíclics: la sirengotoxina i la tiocoralina, amb la finalitat de contribuir en la seva aplicació terapèutica. La sirengotoxina és un lipononadepsipèptid cíclic produït per una bactèria patògena dels arbres cítrics que ha mostrat una interessant activitat contra el paràsit de la Leishmania. En aquest projecte de fàrmac s'ha dissenyat un pèptid anàleg al pèptid natural que conserva els mateixos elements estructurals i la configuració de la cadena peptídico. S'ha obtingut mitjançant una estratègia compatible amb la síntesi del producte natural. En aquesta síntesi s'ha resolt l'obtenció de l'aminoàcid no proteïnogènic així com la seva correcta inserció a la cadena. La tiocoralina és un pèptid bicíclic simètric produït per un microorganisme marí aïllat del corall tou i que presenta una potent activitat com a antitumoral. En aquest projecte s'ha desenvolupat la síntesi d'un anàleg del pèptid natural mitjançant l'aproximació en fase sòlida. En aquest cas, també s'ha resolt la síntesi de dos aminoàcids no proteïnogènics, dues N-metil cisteïnes. Finalment, s'han aïllat nous agents antitumorals d'esponges marines recol·lectades a les costes australianes amb la finalitat d'obtenir nous projectes de fàrmacs així com per ampliar els coneixements en el procés de desenvolupament d'un nou fàrmac.[eng] "Natural Products as a source of new drugs: cyclic depsipeptides synthesis on solid-phase and isolation of antitumoral compounds from marine sponges" TEXT: Natural Products play an important role in the prevention and therapeutic system for human healthy. 50% of drugs in the market are based on natural products and 80% of world depends still from traditional medicine. The drug development process from natural sources is a long and complex way. Recently, several improvements in each step of this process have been determinant for a reinterest from pharmaceutical companies in these kinds of compounds. The chemical synthesis has a relevant role in the drug development process: it allows assuring about identity of compounds, obtaining the bioactive compound in large scale to develop the clinical trial and satisfy the pharmaceutical market demands. The introduction of solid-phase chemistry has been one of the most important improvements in chemical synthesis area because it allows a rapid and efficient exploration about strategic synthetic routes. It has been wide used in peptides and oligonucleotides synthesis and especially useful in cyclic depsipeptides produced by marine microorganism. In the present thesis, is described the development of solid-phase synthesis for two new cyclic depsipeptides, syrengotoxin and thiocoraline with the aim to contribute in its medical use. Syrengotoxin is a cyclic lipononadepsipeptide produced by a pathogen bacterium that shows interesting activity against Leishmania parasite. In this project, it has been designed a analogue peptide which preserve all structural features and the configuration of peptide chain respect natural peptide. The defined synthesis is compatible with syrengotoxin synthesis. It has been developed the non-natural amino acids presents in natural compound and its correct incorporation in the peptide chain. The thiocoraline is a symmetric biclyclic peptide which is produced by a marine microorganism and presents a potent activity as an antitumoral drug. In this project, it has been developed a solid-phase synthesis of a more resistant in plasma analogue. In this case it has been resolved the N-methyl non natural amino acids synthesis that are also present in natural compound. Lastly, it has been isolated new antitumoral compounds from marine sponges collected from south-east Australian coasts which the aim to obtain new drugs and improve the knowledge about drug development from natural sources

‘À La Carte’ Cyclic Hexapeptides: Fine Tuning Conformational Diversity while Preserving the Peptide Scaffold

Cyclic peptides have recently emerged as promising modulators of challenging protein‐protein interactions. Here we report on the design, synthesis and conformational behavior of a small library composed of C2 symmetric cyclic hexapeptides of type c(Xaa‐D‐Pro‐Yaa)2, where Xaa and Yaa are chosen from alanine, isoleucine, serine, glutamic acid, arginine and tryptophan due to the favorable properties of the side chains of these residues to recognize complex protein surfaces. We used a combination of nuclear magnetic resonance and molecular dynamic simulations to perform an extensive conformational analysis of a representative set of cyclic hexapeptides. Our results indicated that both the chemical nature and the chirality of the variable Xaa and Yaa positions play an important role in the cis/trans configuration of the Xaa‐D‐Pro bonds and in the conformational preferences of this family of peptides. This structural tuning can be exploited in design strategies seeking to optimize the binding efficiency and selectivity of cyclic hexapeptides towards protein surfaces

‘À La Carte’ Cyclic Hexapeptides: Fine Tuning Conformational Diversity while Preserving the Peptide Scaffold

Cyclic peptides have recently emerged as promising modulators of challenging protein‐protein interactions. Here we report on the design, synthesis and conformational behavior of a small library composed of C2 symmetric cyclic hexapeptides of type c(Xaa‐D‐Pro‐Yaa)2, where Xaa and Yaa are chosen from alanine, isoleucine, serine, glutamic acid, arginine and tryptophan due to the favorable properties of the side chains of these residues to recognize complex protein surfaces. We used a combination of nuclear magnetic resonance and molecular dynamic simulations to perform an extensive conformational analysis of a representative set of cyclic hexapeptides. Our results indicated that both the chemical nature and the chirality of the variable Xaa and Yaa positions play an important role in the cis/trans configuration of the Xaa‐D‐Pro bonds and in the conformational preferences of this family of peptides. This structural tuning can be exploited in design strategies seeking to optimize the binding efficiency and selectivity of cyclic hexapeptides towards protein surfaces

The isolation of a lipolytic strain of Xanthomonas maltophilia and the cloning of its lipase genes

SIGLEAvailable from British Library Document Supply Centre- DSC:DX95318 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Combined Use of Oligopeptides, Fragment Libraries, and Natural Compounds: A Comprehensive Approach To Sample the Druggability of Vascular Endothelial Growth Factor

The modulation of protein–protein interactions (PPIs) is emerging as a highly promising tool to fight diseases. However, whereas an increasing number of compounds are able to disrupt peptide-mediated PPIs efficiently, the inhibition of domain–domain PPIs appears to be much more challenging. Herein, we report our results related to the interaction between vascular endothelial growth factor (VEGF) and its receptor (VEGFR). The VEGF–VEGFR interaction is a typical domain–domain PPI that is highly relevant for the treatment of cancer and some retinopathies. Our final goal was to identify ligands able to bind VEGF at the region used by the growth factor to interact with its receptor. We undertook an extensive study, combining a variety of experimental approaches, including NMR-spectroscopy-based screening of small organic fragments, peptide libraries, and medicinal plant extracts. The key feature of the successful ligands that emerged from this study was their capacity to expose hydrophobic functional groups able to interact with the hydrophobic hot spots at the interacting VEGF surface patch.This work was supported by the Ministry of Economy and Competitiveness and the European Fund for Regional Development (MINECO-FEDER) (Bio2013-40716-R) and the Generalitat de Catalunya (XRB and 2014-SGR-521). We also thank the NMR facility at the Scientific and Technological Centre of the University of Barcelona (CCiT UB) for their technical support.Peer Reviewe

Combating virulence of Gramnegative bacilli by OmpA inhibition

Preventing the adhesion of pathogens to host cells provides an innovative approach to tackling multidrug-resistant bacteria. In this regard, the identification of outer membrane protein A (OmpA) as a key bacterial virulence factor has been a major breakthrough. The use of virtual screening helped us to identify a cyclic hexapeptide AOA-2 that inhibits the adhesion of Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli to host cells and the formation of biofilm, thereby preventing the development of infection in vitro and in a murine sepsis peritoneal model. Inhibition of OmpA offers a strategy as monotherapy to address the urgent need for treatments for infections caused by Gram-negative bacilli

Combating virulence of Gramnegative bacilli by OmpA inhibition

Preventing the adhesion of pathogens to host cells provides an innovative approach to tackling multidrug-resistant bacteria. In this regard, the identification of outer membrane protein A (OmpA) as a key bacterial virulence factor has been a major breakthrough. The use of virtual screening helped us to identify a cyclic hexapeptide AOA-2 that inhibits the adhesion of Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli to host cells and the formation of biofilm, thereby preventing the development of infection in vitro and in a murine sepsis peritoneal model. Inhibition of OmpA offers a strategy as monotherapy to address the urgent need for treatments for infections caused by Gram-negative bacilli

Combating virulence of Gram-negative bacilli by OmpA inhibition

Preventing the adhesion of pathogens to host cells provides an innovative approach to tackling multidrug-resistant bacteria. In this regard, the identification of outer membrane protein A (OmpA) as a key bacterial virulence factor has been a major breakthrough. The use of virtual screening helped us to identify a cyclic hexapeptide AOA-2 that inhibits the adhesion of Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli to host cells and the formation of biofilm, thereby preventing the development of infection in vitro and in a murine sepsis peritoneal model. Inhibition of OmpA offers a strategy as monotherapy to address the urgent need for treatments for infections caused by Gram-negative bacilli

Combating virulence of Gramnegative bacilli by OmpA inhibition

Preventing the adhesion of pathogens to host cells provides an innovative approach to tackling multidrug-resistant bacteria. In this regard, the identification of outer membrane protein A (OmpA) as a key bacterial virulence factor has been a major breakthrough. The use of virtual screening helped us to identify a cyclic hexapeptide AOA-2 that inhibits the adhesion of Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli to host cells and the formation of biofilm, thereby preventing the development of infection in vitro and in a murine sepsis peritoneal model. Inhibition of OmpA offers a strategy as monotherapy to address the urgent need for treatments for infections caused by Gram-negative bacilli