ABSTRACT
Many microbes produce siderophores, which are extremely potent weapons capable of stealing iron ions from human tissues, fluids and cells and transferring them into bacteria through their appropriate porins. We have recently designed a multi-block molecule, each block having a dedicated role. The first component is an antimicrobial peptide, whose good effectiveness against some bacterial strains was gradually improved through interactive sequence modifications. Connected to this block is a flexible bio-band, also optimized in length, which terminates in a hydroxyamide unit, a strong metal binder. Thus, the whole molecule brings together two pieces that work synergistically to fight infection. To understand if the peptide unit, although modified with a long tail, preserves the structure and therefore the antimicrobial activity, and to characterize the mechanism of interaction with bio-membrane models mimicking Gram-negative membranes, we performed a set of fluorescence-based experiments and circular dichroism studies, which further supported our design of a combination of two different entities working synergistically. The chelating activity and iron(III) binding of the peptide was confirmed by iron(III) paramagnetic NMR analyses, and through a competitive assay with ethylenediamine-tetra acetic acid by ultraviolet-visible spectroscopy. The complexation parameters, the Michaelis constant K, and the number of sites n, evaluated with spectrophotometric techniques are confirmed by Fe(III) paramagnetic NMR analyses here reported. In conclusion, we showed that the coupling of antimicrobial capabilities with iron-trapping capabilities works well in the treatment of infectious diseases caused by Gram-negative pathogens.
ABSTRACT
We have recently witnessed that considerable progresses have been made in the rapid detection and appropriate treatments of COVID-19, but still this virus remains one of the main targets of world research. Based on the knowledge of the complex mechanism of viral infection we designed peptide-dendrimer inhibitors of SARS-CoV-2with the aim to block cell infection through interfering with the host-pathogen interactions. We used two different strategies: i) the first one aims at hindering the virus anchorage to the human cell; ii) the second -strategy points to interfere with the mechanism of virus-cell membrane fusion. We propose the use of different nanosized carriers, formed by several carbosilane dendritic wedges to deliver two different peptides designed to inhibit host interaction or virus entry. The antiviral activity of the peptide-dendrimers, as well as of free peptides and free dendrimers was evaluated through the use of SARS-CoV-2 pseudotyped lentivirus. The results obtained show that peptides designed to block host-pathogen interaction represent a valuable strategy for viral inhibition.
ABSTRACT
The engineering of intracellular delivery systems with the goal of achieving personalized medicine has been encouraged by advances in nanomaterial science as well as a greater understanding of diseases and of the biochemical pathways implicated in many disorders. The development of vectors able to transport the drug to a target location and release it only on demand is undoubtedly the primary issue. From a molecular perspective, the topography of drug carrier surfaces is directly related to the design of an effective drug carrier because it provides a physical hint to modifying its interactions with biological systems. For instance, the initial ratio of hydrophilic to hydrophobic surfaces and the changes brought about by external factors enable the release or encapsulation of a therapeutic molecule and the ability of the nanosystem to cross biological barriers and reach its target without causing systemic toxicity. The first step in creating new materials with enhanced functionality is to comprehend and characterize the interplay between hydrophilic and hydrophobic molecules at the molecular level. Therefore, the focus of this review is on the function of hydrophobicity, which is essential for matching the complexity of biological environments with the intended functionality.
Subject(s)
Drug Carriers , Drug Delivery Systems , Hydrophobic and Hydrophilic Interactions , Drug Carriers/chemistryABSTRACT
Numerous supramolecular platforms inspired by natural self-assembly are exploited as drug delivery systems. The spontaneous arrangement of single building blocks into inorganic and organic structures is determined and controlled by noncovalent forces such as electrostatic interactions, π-π interactions, hydrogen bonds, and van der Waals interactions. This review describes the main structures and characteristics of several building blocks used to obtain stable, self-assembling nanostructures tailored for numerous biological applications. Owing to their versatility, biocompatibility, and controllability, these nanostructures find application in diverse fields ranging from drug/gene delivery, theranostics, tissue engineering, and nanoelectronics. Herein, we described the different approaches used to design and functionalize these nanomaterials to obtain selective drug delivery in a specific disease. In particular, the review highlights the efficiency of these supramolecular structures in applications related to infectious diseases and cancer.
ABSTRACT
Antimicrobial peptides (AMPs) have recently gained attention as a viable solution for combatting antibiotic resistance due to their numerous advantages, including their broad-spectrum activity, low propensity for inducing resistance, and low cytotoxicity. Unfortunately, their clinical application is limited due to their short half-life and susceptibility to proteolytic cleavage by serum proteases. Indeed, several chemical strategies, such as peptide cyclization, N-methylation, PEGylation, glycosylation, and lipidation, are widely used for overcoming these issues. This review describes how lipidation and glycosylation are commonly used to increase AMPs' efficacy and engineer novel AMP-based delivery systems. The glycosylation of AMPs, which involves the conjugation of sugar moieties such as glucose and N-acetyl galactosamine, modulates their pharmacokinetic and pharmacodynamic properties, improves their antimicrobial activity, and reduces their interaction with mammalian cells, thereby increasing selectivity toward bacterial membranes. In the same way, lipidation of AMPs, which involves the covalent addition of fatty acids, has a significant impact on their therapeutic index by influencing their physicochemical properties and interaction with bacterial and mammalian membranes. This review highlights the possibility of using glycosylation and lipidation strategies to increase the efficacy and activity of conventional AMPs.
ABSTRACT
Chronic lung infections in cystic fibrosis (CF) patients are triggered by multidrug-resistant bacteria such as Pseudomonas aeruginosa, Achromobacter xylosoxidans, and Stenotrophomonas maltophilia. The CF airways are considered ideal sites for the colonization and growth of bacteria and fungi that favor the formation of mixed biofilms that are difficult to treat. The inefficacy of traditional antibiotics reinforces the need to find novel molecules able to fight these chronic infections. Antimicrobial peptides (AMPs) represent a promising alternative for their antimicrobial, anti-inflammatory, and immunomodulatory activities. We developed a more serum-stable version of the peptide WMR (WMR-4) and investigated its ability to inhibit and eradicate C. albicans, S. maltophilia, and A. xylosoxidans biofilms in both in vitro and in vivo studies. Our results suggest that the peptide is able better to inhibit than to eradicate both mono and dual-species biofilms, which is further confirmed by the downregulation of some genes involved in biofilm formation or in quorum-sensing signaling. Biophysical data help to elucidate its mode of action, showing a strong interaction of WMR-4 with lipopolysaccharide (LPS) and its insertion in liposomes mimicking Gram-negative and Candida membranes. Our results support the promising therapeutic application of AMPs in the treatment of mono- and dual-species biofilms during chronic infections in CF patients.
