1. Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies
Rafał J Kopiasz, Natalia Kulbacka, Karolina Drężek, Rafał Podgórski, Ilona Łojszczyk, Jolanta Mierzejewska, Tomasz Ciach, Ewa Augustynowicz-Kopeć, Agnieszka Głogowska, Agnieszka Iwańska, Waldemar Tomaszewski, Dominik Jańczewski Macromol Biosci. 2022 Jul;22(7):e2200094.doi: 10.1002/mabi.202200094.Epub 2022 May 18.
An alarming increase of antibiotic resistance among pathogens creates an urgent need to develop new antimicrobial agents. Many reported polycations show high antimicrobial activity along with low hemolytic activity. Unfortunately, most of those molecules remain highly cytotoxic against various mammalian cells. In this work, a systematic study on the impact of triethylene glycol monomethyl ether side groups (short polyethylene glycol (PEG) analog) on antimicrobial, hemolytic, and cytotoxic properties of novel amphiphilic ionenes is presented. A detailed description of synthesis, leading to well-defined alternating polymers, which differ in structural elements responsible for hydrophilicity (PEG) and hydrophobicity (alkyl chain), is presented. Obtained results show that the PEG moiety and fine-tuned hydrophilic-lipophilic balance of ionenes synergistically lead to low cytotoxic, low hemolytic molecules with high activity against S. aureus, including methicillin-resistant strains (MRSA). Additionally, the results of mechanistic studies on bacterial cells and fluorescently labeled liposomes are also discussed.
2. Conjugation of carbohydrates to proteins using di(triethylene glycol monomethyl ether) squaric acid ester revisited
Peng Xu, Michael N Trinh, Pavol Kováč Carbohydr Res. 2018 Feb 1;456:24-29.doi: 10.1016/j.carres.2017.10.012.Epub 2017 Nov 7.
Properties of di(triethylene glycol monomethyl ether) squarate relevant to conjugation of carbohydrates to proteins have been reinvestigated and compared with those of dimethyl squarate. It is concluded that the commercially available, crystalline dimethyl squarate remains the most convenient and efficient reagent for conjugation of amine-containing carbohydrates to proteins by a two-step or one-pot conjugation protocol.
3. Role of peroxynitrite in the cardiovascular dysfunction of septic shock
Lucas Liaudet, Nathalie Rosenblatt-Velin, Pal Pacher Curr Vasc Pharmacol. 2013 Mar 1;11(2):196-207.
The intense systemic inflammatory response characterizing septic shock is associated with an increased generation of free radicals by multiple cell types in cardiovascular and non cardiovascular tissues. The oxygen-centered radical superoxide anion (O2 .-) rapidly reacts with the nitrogen-centered radical nitric oxide (NO.) to form the potent oxidant species peroxynitrite. Peroxynitrite oxidizes multiple targets molecules, either directly or via the secondary generation of highly reactive radicals, resulting in significant alterations in lipids, proteins and nucleic acids, with significant cytotoxic consequences. The formation of peroxynitrite is a key pathophysiological mechanism contributing to the cardiovascular collapse of septic shock, promoting vascular contractile failure, endothelial and myocardial dysfunction, and is also implicated in the occurrence of multiple organ dysfunction in this setting. The recent development of various porphyrin-based pharmacological compounds accelerating the degradation of peroxynitrite has allowed to specifically address these pathophysiological roles of peroxynitrite in experimental septic shock. Such agents, including 5,10,15,20-tetrakis(4- sulfonatophenyl)porphyrinato iron III chloride (FeTTPs), manganese tetrakis(4-N-methylpyridyl)porphyrin (MnTMPyP), Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin) (FP-15) and WW-85, have been shown to improve the cardiovascular and multiple organ failure in small and large animal models of septic shock. Therefore, these findings support the development of peroxynitrite decomposition catalysts as potentially useful novel therapeutic agents to restore cardiovascular function in sepsis.
