In this paper, we propose a new strategy for the development of synthetic amino acid transporters. Such molecules might be expected to display a wide range of biological activities and also find applications in drug delivery, metabolism regulation, and as next-generation antibiotics.
The transport of amino acids across biological membranes is vital for the proper functioning of every living cell. This is because at physiological pH amino acids are very polar (they have a positively charged N-terminus and a negatively charged C-terminus) and therefore cannot pass through lipid bilayers alone. In nature, amino acid transport is carried out by specialized membrane proteins that play important roles in regulating key physiological functions, such as protein biosynthesis, metabolism, gene expression, redox balance and signaling. The dysfunction of these proteins contributes to the development of serious diseases, such as diabetes, neurodegenerative disorders, obesity and cancer. Synthetic amino acid transporters could help in treating these diseases, and might also find applications in drug delivery, metabolism regulation, and as next-generation antibiotics.
Unfortunately, precisely because amino acids are both cations and anions, the development of such synthetic amino acid transporters has so far been extremely difficult, since it required combining both cation and anion binding sites in one structure. In this paper, however, we show that this is not the only possible strategy and that even very simple anion transporters are able to efficiently transport amino acids across lipid bilayers at physiological pH. To explain this unexpected effectiveness of simple anionophores, we developed a new assay for studying the transport of amino acids, that gave us insight into the mechanism of this phenomenon. As a result, we were able to propose a new strategy to search for synthetic amino acid transporters with improved properties and interesting biological activity. Read on here.
The study reveals two distinct HCO3‾ transport mechanisms by simple di(thio)amidocarbazoles as well as their potent antimicrobial properties. Read more here.
Anions are typically too hydrophilic to freely pass through biological membranes. This also applies to those drugs that are anionic at physiological pH. Synthetic anion transporters, i.e. small, lipophilic molecules that facilitate diffusion of anions across lipophilic barriers, may accelerate the diffusion of anionic drugs by many orders of magnitude and thus could dramatically increase their effectiveness. Moreover, transporters whose activity could be controlled by light, pH or other stimuli could enable the targeted delivery of drugs to the desired place and at the right time. The aim of this project is to develop the first switchable transporters for anionic drugs, and hence to demonstrate a new strategy for targeted drug delivery. As part of it, we will undertake research on the construction of transporters switchable by changes in pH or irradiation with light of a specific wavelength. We hope that this research will lead to the development of a new strategy for smart drug delivery, which may find practical applications in the future, e.g. in the treatment of cancer.
A most warming welcome to our new post-doc: Dr. Debashis Mondal!
Debashis did his M.Sc. in chemistry from IIT Bombay (India) in 2015. He then enrolled at IISER Pune (India) for his doctoral studies in 2016, where he studied in the subfield of supramolecular chemistry under the supervision of Prof. Pinaki Talukdar. After completing his Ph.D. graduation in 2022, he joined the Supramolecular Chemistry group of Prof. Michał J. Chmielewski at the University of Warsaw as a post-doctoral fellow in September 2022.
Social media profile: https://twitter.com/DebashisJMChem
We are looking for 2 postdoctoral researchers for a groundbreaking research project on the border of organic, medicinal, and supramolecular chemistry.
The aim of the project is to develop small organic molecules capable of selectively transporting biologically relevant anions through lipid bilayers. Such molecules may exhibit interesting anti-cancer, antibacterial and antiviral properties, and may also find applications in the treatment of numerous diseases resulting from the dysfunction of natural transporters. Within the project, we would also like to construct stimuli-responsive transporters whose activity could be controlled by pH, light, or redox potential.
Successful candidates will design and synthesize novel anion receptors, study their anion binding properties and investigate their ability to transport anions through the lipid bilayers of model liposomes.
Deadline for applications: 16 July 2022. More details in the following Announcement.
Chloride transporters have been intensely investigated because of their potential medicinal applications. In particular, pH-switchable transporters are highly appealing as potential anticancer agents, because they might be more active in cancer cells than in normal cells. Owing to its increased acidity, our simple 3,6-dinitro substituted carbazole receptor acts as a pH-switchable transporter, with physiologically relevant apparent pKa of 6.4. Read more in our newest paper in special issue of Frontiers in Chemistry, devoted to anion transport:
Maslowska-Jarzyna, M. L. Korczak, M. J. Chmielewski, “Boosting Anion Transport Activity of Diamidocarbazoles by Electron Withdrawing Substituents” Front. Chem., 2021, 9:690035.
We invite students interested in collaboration on a ground-breaking research project on the border of organic and material chemistry. Attractive fellowships are available!
Poszukujemy studentów do współpracy przy realizacji przełomowego projektu badawczego z pogranicza chemii organicznej i materiałowej. Atrakcyjne stypendia czekają!
Celem projektu jest stworzenie zupełnie nowej klasy ‘inteligentnych’ materiałów porowatych, łączących trwałość MOF-ów ze zdolnością do odpowiedzi na bodźce i adaptacji do środowiska zewnętrznego. W ramach projektu zamierzamy też opracować nową strategię konstruowania MOF-ów przewodzących prąd elektryczny do zastosowań w bateriach i superkondensatorach.
Termin nadsyłania zgłoszeń – 10.12.2021. Więcej szczegółów tu: Ogłoszenie.
Electrically conductive metal-organic frameworks (MOFs) are a fascinating class of porous conductors with many potential applications, such as chemiresistive sensing, electrochemical energy storage, and electrocatalysis. Owing to the Bekker fellowship from the Polish National Agency for Academic Exchange (NAWA), Dr. Michał Chmielewski spent 7 months in the laboratory of one of the pioneers and leaders of the development of these materials, prof. Mircea Dincă from Massachusetts Institute of Technology. The first results of this collaboration have just appeared in Angewandte Chemie International Edition:
Drugs, metabolites, and other biologically relevant anionic species can be rapidly transported through biological membranes by a simple di(thioamide) receptor developed in our laboratory. In collaboration with the group of professor Alexander Kros from Leiden University, we have also shown that the transport kinetics of these anions can be easily quantified in both large and giant unilamellar vesicles (LUVs and GUVs).