PhD Project for Research Scholarships Application ITQB NOVA
Supervisors: Ana Petronilho (Supervisor, ITQB NOVA), Salette Reis (co-Supervisor, FF University of Porto)
Project Title: Targeting Metallodrug Delivery Through Encapsulation
Abstract: Platinum-based anticancer drugs2 are responsible for circa 50 % of all anticancer therapies worldwide3. One of the biggest challenges is to minimize side effects and overcome resistance associated with platinum-based treatments. Very often, a significant part of the drug reacts or decomposes before reaching its target, requiring the use of very high concentrations, that lead to severe side effects and contribute to drug resistance. In this PhD project, we will develop novel strategies for the synthesis and targeted delivery of metallodrugs, while keeping the integrity of the drug. To achieve this, we will utilize encapsulation methodologies combined with molecular recognition strategies.
The efficiency and efficacy of metallodrugs in medicinal chemistry is frequently halted by the difficulty of reaching the desired target. Very often, a significant part of drug reacts or decomposes during this pathway. One possible strategy to overcome this problem is to develop novel strategies that warrant delivery while keeping the drug intact and able to interact with its target. Methodologies for drug encapsulation are known ( see for instance Int. J. Nanomedicine, 2019; Eur J Pharm Sci, 2018) and have proven efficient in the controlled drug release. Yet, for metallodrugs encapsulation strategies are still scarce, despite the widespread use of metallodrugs and the well-known side effects associated with a number of them, in particular platinum based anti-cancer agents.
In this project we aim to tackle this problem by developing novel strategies for anticancer-drug development and encapsulation. We will exploit the synthesis of metal complexes based on anticancer-active nucleosides (e.g. gemcitabine) to promote a dual modus operandi within the metallodrug. Recent work from Petronilho’s Lab has demonstrated that nucleoside-based complexes of platinum and palladium are active compounds against a number of cell lines (ACS OMEGA, 2018) while being non-toxic for healthy cells. These complexes are also able to promote molecular recognition via base pairing (Chem. Comm. 2020). With these effective compounds, we will explore methods for encapsulation and delivery to specific targets, following the long standing expertise of the co-supervisor (S. Reis) on encapsulation and targeted drug delivery of nanoparticles.
With this approach we combine
i) The synergies between:
a. antimetabolite cytotoxic effect of the modified nucleoside
b. A late transition metal with a well-known cytotoxic platform
c. Targeted delivery, trough the formation of nanoparticles via encapsulation.
While some of these approaches have been explored individually, they have not, to the best of our knowledge, been merged, and as such are unprecedented.
Supervisors: Beatriz Royo, Organometallic Catalysis Group, ITQB NOVA (Supervisor), Paula Gomes (co-Supervisor, University of Porto), and Paula Gameiro (co-Supervisor, University of Porto).
Title: Organometallic-Peptide Bioconjugates as New Antimicrobial Agents
Abstract : This project aims to develop new mangenese and ruthenium-based organometallic-peptide conjugates for their application as antimicrobial agents. Antimicrobial resistance has been identified by the World Health Organization as one of the greatest current threats to global health. To meet the societal need for effective treatments, scientists are searching for new classes of antimicrobial compounds with completly new modes of action. Our strategy is the modification of simple antimicrobial peptides (AMPs) with organometallic complexes (OM) for the preparation of organometallic AMPs (OM-AMPs). We anticipate that such agents could become important players in the discover of new antibiotics. This multidisciplinary project will combine the expertise of three groups on organometallic chemistry (B. Royo), peptide chemistry (P. Gomes), and bioinorganic approaches to tackle antibiotic resistance (P. Gameiro).
Description of project
During the last decade, the number of antimicrobial agents that have been discoved and reached the market has declined. Therefore, there is an urgent need to search for new classes of antimicrobial compounds with new modes of action. Currently, most of the efforts are directed toward the modification of existing antibiotics, but ideally, compounds with new mechanims of action are required. Metal complexes are an attractive class of molecules with potential application as antibacterial agents. Recently, the group of Royo has developed new families of Mn(I) and Ru(II) complexes containing N-heterocyclic carbene (NHCs) ligands that displayed promising activity as antimicrobial agents. On the other hand, peptides are important biological molecular entities in biomedical reasearch. The groups of P. Gomes and P. Gameiro have been devoted to the development and study of peptide and non-peptide based organic and organometallic molecules to fight infectious diseases for over two decades; recent joint achievements of these two group leaders within LAQV-REQUIMTE include development of hybrid peptides with dual antimicrobial and wound-healing action and peptide-ionic liquid conjugates with increased resistance to enzymatic degradation. The project will address three main tasks: (i) development of synthetic strategies for the conjugation of the OM to the selected AMPs; (ii) characterization of the new OM-AMPs by a toolbox of structural analysis techniques, and (iii) in vitro evaluation of OM-AMPs’ activity against Gram+ and Gram- bacteria, including both susceptible reference strains and multidrug-resistant clinical isolates.
Supervisor : Rita Ventura, Bioorganic Chemistry Group, ITQB NOVA
Project Title: Synthesis of new recyclable catalysts for stereoselective synthesis
Abstract: Organocatalysis is an important area of modern catalysis. A rapidly growing number of publications describing the new organocatalysed reactions and the development of new organocatysts can be found. Synthetic chemists have started to look at organocatalysis as a valuable tool for the asymmetric total synthesis of natural products and biological active compounds. As no metals are involved the potential for green industrial applications is very attractive and indeed several pharmaceutical industries are using organocatalysts in their syntheses.
However, being homogeneous catalysts, their recovery and reuse is a problem. The aim of this project is the synthesis of organocatalysts attached to different supports, their validation in several enantioselective reactions and their application in the total synthesis of selected biological important compounds.