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Improving natural products chemical biodiversity for drug discovery by fungal secretome assisted biotransformation

English title Improving natural products chemical biodiversity for drug discovery by fungal secretome assisted biotransformation
Applicant Ferreira Queiroz Emerson
Number 182438
Funding scheme Project funding (Div. I-III)
Research institution Université de Genève Chimie Appliquée Sciences II
Institution of higher education University of Geneva - GE
Main discipline Organic Chemistry
Start/End 01.04.2019 - 31.03.2023
Approved amount 319'161.00
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All Disciplines (2)

Discipline
Organic Chemistry
Biochemistry

Keywords (7)

Biotransformation; Fungal secretome; Chemical biodiversity; Fungal enzymes; Biological activity; Natural products; Fungi

Lay Summary (French)

Lead
L'objectif de ce projet est d'étudier la transformation de produits naturels (PNs) à l'aide de mélanges d’enzymes secrétées par diverses espèces de champignons provenant d’environnements variés. Ces biotransformations permettront de produire de nouvelles molécules, d’accroitre leur diversité chimique et de cette façon d'obtenir des composés biologiquement actifs novateurs.
Lay summary

Contenu et objectifs du travail de recherche

Durant ce projet, nous nous proposons de construire, par biotransformation enzymatique, une bibliothèque de PNs originaux. Dans une première phase, nous étudierons, à petite échelle, les réactions de biotransformation d’une série de PNs par un éventail d’enzymes fongiques. Au cours d’une deuxième phase, nos recherches s’intéresseront à reproduire certaines réactions à plus grande échelle afin de pouvoir isoler et caractériser les composés générés. Dans une troisième phase les composés obtenus seront soumis à des essais d’activité antifongique, antibactérienne, anti-inflammatoire et de toxicité cellulaire. Nos recherches aideront à mieux comprendre le potentiel des réactions enzymatiques pour la production de nouveaux PNs biologiquement actifs.

 

Contexte scientifique et social du projet de recherche

Comme les PNs sélectionnées pour les biotransformations proviennent principalement de plantes ou de micro-organismes cultivés en Suisse, la méthodologie proposée permettra de surmonter les problèmes liés à l'accès aux plantes et au partage des bénéfices imposés par la Convention sur la biodiversité. De plus, cette approche pourrait apporter une solution au problème de réapprovisionnement des PNs souvent considéré par les compagnies pharmaceutiques comme un obstacle majeur à la découverte de médicaments basés sur la chimie des PNs. Les résultats préliminaires obtenus démontrent la capacité de ces réactions de biotransformation à produire une grande diversité chimique à partir des PNs.

Direct link to Lay Summary Last update: 07.02.2019

Responsible applicant and co-applicants

Employees

Name Institute

Project partner

Associated projects

Number Title Start Funding scheme
164095 NMR 600MHz for metabolomics and biomarker identification for life sciences, chemical biology and medical projects at the University of Geneva 01.01.2016 R'EQUIP

Abstract

Natural products (NPs) have been the starting point for the development of large number of therapeutics along the history. According to Newman and Cragg (2016), an important percentage of small-molecule new chemical entities registered as drugs worldwide during the period of 1981-2014 were NPs or were inspired by NPs. The classical way to obtain bioactive natural products is the bioassay-guided fractionation of an active extract from plant or microbial origin. This strategy is based on the separation of the constituents using different chromatographic steps combined with biological assays, aiming at the isolation and identification of the compound(s) responsible for a given biological activity. While being very successful for the discovery of important drugs such as artemisinin (Nobel prize of Physiology or Medicine in 2015) this approach is challenging due to (i) low yields of the isolated compounds, (ii) limited supply, (iii) limitation of targeted structural modification due to the structure complexity and (iv) difficulty of total synthesis due to structural complexity. These technical difficulties led the pharmaceutical industry to develop new technologies during the past two decades, particularly with respect to combinatorial chemistry, but also at the detriment of interest in natural product discovery. These synthetic approaches did however not succeed to provide new drugs partly related to limited chemical space so that there is a need to reconsider NPs for drug discovery by developing new strategies. In this context, biotransformation reactions represent an interesting alternative to obtain NP derivatives covering a large chemical space from sustainable sources. With this project, we propose to build a library of “unnatural” natural products (“unnatural” NPs) obtained by biotransformation that could be used in the frame of biological screening campaigns. Rather than using an intact microorganism or a pure enzyme to perform the biotransformation, the idea and novelty is to biotransform NPs by the secretome of given fungi (mixture of their enzymes) in order to obtain original chemically diverse unnatural NPs using both untargeted and semi-targeted enzymatic reactions. The biological activity of the “unnatural” NPs generated will be evaluated in a first instance on antifungal, antibacterial, anti-inflammatory assays as well as cellular toxicity. As a perspective, the most promising active compounds will be used as a model for the selection of potential new NPs candidates for biotransformation. In addition, the structural database of the new scaffolds generated will be made available for further in silico evaluation of their bioactive potential in a wide range of targets. This project is expected to yield important information on the biotransformation potential of a collection of fungal secretomes. Thanks to this innovative biotransformation strategy applied to selected NPs, it is anticipated that an original collection of “unnatural” NPs will be created that may present interesting biological activities. The systematic biochemical investigation of the various collections of fungal secretomes within this project may also yield original functional information on given fungal species. This research project combines the complementary expertise of two different laboratories in both natural product chemistry and mycology and extends to different partners for specific bioassay evaluation.
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