Inhibiting The uPA/uPAR Pathway Affords Photoreceptor Resilience and Preserves Retinal Function in a Mouse Model of Retinitis Pigmentosa.

Purpose: Retinitis pigmentosa (RP) is characterized by primary rod degeneration followed by secondary cone death. The urokinase-type plasminogen activator (uPA) and its cognate receptor (uPAR) have been recently suggested to regulate pro-inflammatory events in RP possibly through the interaction of uPAR with its lateral partners, including formyl peptide receptors (FPRs). This study explored whether the inhibition of the crosstalk between uPAR and FPR1 may counteract photoreceptor degeneration in the rd10 mouse model of RP.

Potential targeting of urokinase-type plasminogen activator receptor-formyl peptide receptor signaling to prevent recurrence in posttransplant primary podocytopathies.

Primary podocytopathies are a group of disorders characterized by nephrotic syndrome and frequent progression to kidney failure, with high rates of posttransplant recurrence. Increased expression of the urokinase-type plasminogen activator receptor (uPAR) has been associated with podocyte dysfunction in primary podocytopathies. uPAR can interact with formyl peptide receptors (FPRs) in podocytes, but the relevance of this signaling pathway in these diseases remains unclear.

Synthesis of a di-O-acylated deoxynojirimycin (DNJ) derivative and evaluation of its antibacterial and antibiofilm activity against Staphylococcus aureus and Stenotrophomonas maltophilia.

Herein we report the synthesis of a novel di-O-acylated DNJ derivative, conceived to study whether iminosugar derivatization with a lipophilic acyl moiety could positively affect its antibacterial properties. The well-known PS-TPP/I/ImH activating system was used to readily install the acyl chains on the iminosugar, leading to the desired compound in high yield. Biological assays revealed that a di-O-lauroyl DNJ derivative enhanced the antibacterial effect of gentamicin and amikacin against S.

Turn-Adopting Peptidomimetic as a Formyl Peptide Receptor-1 Antagonist.

The design, synthesis, and characterization of a new peptidomimetic acting as a formyl peptide receptor (FPR1) antagonist (N-19004) are herein reported. The molecule has been identified with docking studies of the highly potent FPR1 antagonist UPARANT on human receptor. N-19004 recapitulates all pharmacophoric groups necessary for recognition into a minimal structure, with a crucial role of the 2,6-diamino-thiophenyl scaffold mimicking the positions of Cα atoms of Arg residues in the turned Arg-Aib-Arg segment of UPARANT.

Synthesis of Natural and Sugar-Modified Nucleosides Using the Iodine/Triethylsilane System as -Glycosidation Promoter.

The reagent system based on the combined use of EtSiH/I acts as an efficient -glycosidation promoter for the synthesis of natural and sugar-modified nucleosides. An analysis of reaction stereoselectivity in the absence of C2-positioned stereodirecting groups revealed high selectivity with six-membered substrates, depending on the nucleophilic character of the nucleobase or based on anomerization reactions. The synthetic utility of the EtSiH/I-mediated -glycosidation reaction was highlighted by its use in the synthesis of the investigational drug apricitabine.

Peptide-based metalloporphyrin catalysts: unveiling the role of the metal ion in indole oxidation.

Over the last decades, much effort has been devoted to the construction of protein and peptide-based metalloporphyrin catalysts capable of promoting difficult transformations with high selectivity. In this context, mechanistic studies are fundamental to elucidate all the factors that contribute to catalytic performances and product selectivity. In our previous work, we selected the synthetic peptide-porphyrin conjugate MnMC6*a as a proficient catalyst for indole oxidation, promoting the formation of a 3-oxindole derivative with unprecedented selectivity.

Selective Oxidation of Halophenols Catalyzed by an Artificial Miniaturized Peroxidase.

The development of artificial enzymes for application in sustainable technologies, such as the transformation of environmental pollutants or biomass, is one of the most challenging goals in metalloenzyme design. In this work, we describe the oxidation of mono-, di-, tri- and penta-halogenated phenols catalyzed by the artificial metalloenzyme Fe-MC6*a. It promoted the dehalogenation of 4-fluorophenol into the corresponding 1,4-benzoquinone, while under the same experimental conditions, 4-chloro, 4-bromo and 4-iodophenol were selectively converted into higher molecular weight compounds.

-Substituted l-Iminosugars for the Treatment of Sanfilippo Type B Syndrome.

Sanfilippo syndrome comprises a group of four genetic diseases due to the lack or decreased activity of enzymes involved in heparan sulfate (HS) catabolism. HS accumulation in lysosomes and other cellular compartments results in tissue and organ dysfunctions, leading to a wide range of clinical symptoms including severe neurodegeneration. To date, no approved treatments for Sanfilippo disease exist.

Synthesis and antiviral properties of biomimetic iminosugar-based nucleosides.

Herein we report the synthesis, conformational analysis and the evaluation of the antiviral activity of six-membered nucleoside analogues having a piperidine ring as the preorganized (deoxy)ribose bioisostere. Mutagenic nucleobase-containing nucleosides 1 and 2 were obtained by appropriate manipulation of the well-known glycomimetic agent deoxynojirimycin as easily accessible starting material. In vitro assays revealed activity of 5-iododeoxyuridine analogue 1 against all DNA viruses tested.

Oxidative dehalogenation of trichlorophenol catalyzed by a promiscuous artificial heme-enzyme.

The miniaturized metalloenzyme Fe(iii)-mimochrome VI*a (Fe(iii)-MC6*a) acts as an excellent biocatalyst in the HO-mediated oxidative dehalogenation of the well-known pesticide and biocide 2,4,6-trichlorophenol (TCP). The artificial enzyme can oxidize TCP with a catalytic efficiency ( / = 150 000 mM s) up to 1500-fold higher than the most active natural metalloenzyme horseradish peroxidase (HRP). UV-visible and EPR spectroscopies were used to provide indications of the catalytic mechanism.

Synthesis of Piperidine Nucleosides as Conformationally Restricted Immucillin Mimics.

The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation.

Toward the Identification of Novel Antimicrobial Agents: One-Pot Synthesis of Lipophilic Conjugates of -Alkyl d- and l-Iminosugars.

In the effort to improve the antimicrobial activity of iminosugars, we report the synthesis of lipophilic iminosugars - and - based on the one-pot conjugation of both enantiomeric forms of -butyldeoxynojirimycin (NBDNJ) and -nonyloxypentyldeoxynojirimycin (NPDNJ) with cholesterol and a succinic acid model linker. The conjugation reaction was tuned using the established PS-TPP/I/ImH activating system, which provided the desired compounds in high yields (94-96%) by a one-pot procedure. The substantial increase in the lipophilicity of - and - is supposed to improve internalization within the bacterial cell, thereby potentially leading to enhanced antimicrobial properties.

Pharmacokinetics of the Urokinase Receptor-Derived Peptide UPARANT After Single and Multiple Doses Administration in Rats.

Background And Objectives: UPARANT has emerged as a novel therapeutic agent with the potential to treat ocular diseases as assessed by studies in animal models. Since limited information is available on the pharmacokinetics of UPARANT, the aim of this study is to evaluate its pharmacokinetics after single and multiple ascending dose (SAD and MAD) administration in rats.

Methods: Male (n = 27) and female (n = 27) Sprague-Dawley rats were divided into six groups (n = 9/sex/group).

-Nonyloxypentyl-l-Deoxynojirimycin Inhibits Growth, Biofilm Formation and Virulence Factors Expression of .

is one of the major causes of hospital- and community-associated bacterial infections throughout the world, which are difficult to treat due to the rising number of drug-resistant strains. New molecules displaying potent activity against this bacterium are urgently needed. In this study, d- and l-deoxynojirimycin (DNJ) and a small library of their -alkyl derivatives were screened against ATCC 29213, with the aim to identify novel candidates with inhibitory potential.

COVID-19 and pneumonia: a role for the uPA/uPAR system.

Here, we highlight recent findings on the urokinase plasminogen activator (uPA)/uPA receptor (uPAR) system that suggest its potential role as a main orchestrator of fatal progression to pulmonary, kidney, and heart failure in patients with coronavirus. Patients with prolonged background inflammation can present aberrant inflammatory reactions, well recognized as the main factors that can result in death and probably sustained by a dysregulated uPA/uPAR system. SuPAR, the soluble form of uPAR, represents a biomarker of disease progression, and its levels correlate well with comorbidities associated with the death of patients with coronavirus.

Synthesis and Therapeutic Applications of Iminosugars in Cystic Fibrosis.

Iminosugars are sugar analogues endowed with a high pharmacological potential. The wide range of biological activities exhibited by these glycomimetics associated with their excellent drug profile make them attractive therapeutic candidates for several medical interventions. The ability of iminosugars to act as inhibitors or enhancers of carbohydrate-processing enzymes suggests their potential use as therapeutics for the treatment of cystic fibrosis (CF).

Structure-Activity Relationship Study of a Potent α-Thrombin Binding Aptamer Incorporating Hexitol Nucleotides.

The replacement of one or more nucleotide residues in the potent α-thrombin-binding aptamer NU172 with hexitol-based nucleotides has been devised to study the effect of these substitutions on the physicochemical and functional properties of the anticoagulant agent. The incorporation of single hexitol nucleotides at the T9 and G18 positions of NU172 substantially retained the physicochemical features of the parent oligonucleotide, as a result of the biomimetic properties of the hexitol backbone. Importantly, the NU172-T 9 mutant exhibited a higher binding affinity toward human α-thrombin than the native aptamer and an improved stability even after 24 h in 90 % human serum, with a significant increase in the estimated half-life.

Steroid Derivatives as Potential Antimicrobial Agents Against Planktonic Cells.

In this work, the antibacterial activity of deflazacort and several of its synthetic precursors was tested against a panel of bacterial pathogens responsible for most drug-resistant infections including spp., , , , , and spp. The derivative of deflazacort, PYED-1 (pregnadiene-11-hydroxy-16α,17α-epoxy-3,20-dione-1) showed the best antibacterial activity in a dose-dependent way.

Antibacterial and Antivirulence Activity of Glucocorticoid PYED-1 against .

, an environmental Gram-negative bacterium, is an emerging nosocomial opportunistic pathogen that causes life-threatening infections in immunocompromised patients and chronic pulmonary infections in cystic fibrosis patients. Due to increasing resistance to multiple classes of antibiotics, infections are difficult to treat successfully. This makes the search for new antimicrobial strategies mandatory.

A Stereoconvergent Tsuji-Trost Reaction in the Synthesis of Cyclohexenyl Nucleosides.

A highly regio- and stereoselective route to d- and l-cyclohexenyl nucleosides has been devised, using the Tsuji-Trost reaction as the key step. Contrarily to the widely accepted mechanism (involving a net retention of configuration), the reaction proceeded in a highly stereoconvergent manner, providing cis nucleosides regardless of the relative configuration of the starting materials. DFT calculations confirmed the experimental data while suggesting the origin of the stereochemical reaction outcome.

Engineering Metalloprotein Functions in Designed and Native Scaffolds.

Metalloproteins are crucial for life. The mutual relationship between metal ions and proteins makes metalloproteins able to accomplish key processes in biological systems, often very difficult to reproduce with inorganic coordination compounds under mild conditions. Taking inspiration from nature, many efforts have been devoted to developing artificial molecules as metalloprotein mimics.

Expeditious synthesis and preliminary antimicrobial activity of deflazacort and its precursors.

The synthesis of deflazacort (DFZ) and a preliminary evaluation of its microbial activity against the human pathogens and is herein reported. While DFZ is inactive, one of its synthetic precursors showed a strong antibacterial activity against both Gram-negative and -positive bacteria.

Exploring the effect of chirality on the therapeutic potential of N-alkyl-deoxyiminosugars: anti-inflammatory response to Pseudomonas aeruginosa infections for application in CF lung disease.

In the frame of a research program aimed to explore the relationship between chirality of iminosugars and their therapeutic potential, herein we report the synthesis of N-akyl l-deoxyiminosugars and the evaluation of the anti-inflammatory properties of selected candidates for the treatment of Pseudomonas aeruginosa infections in Cystic Fibrosis (CF) lung disease. Target glycomimetics were prepared by the shortest and most convenient approach reported to date, relying on the use of the well-known PS-TPP/I reagent system to prepare reactive alkoxyalkyl iodides, acting as key intermediates. Iminosugars ent-1-3 demonstrated to efficiently reduce the inflammatory response induced by P.

Mn-Mimochrome VIa: An Artificial Metalloenzyme With Peroxygenase Activity.

Manganese-porphyrins are important tools in catalysis, due to their capability to promote a wide variety of synthetically valuable transformations. Despite their great reactivity, the difficulties to control the reaction selectivity and to protect the catalyst from self-degradation hamper their practical application. Compared to small-molecule porphyrin complexes, metalloenzymes display remarkable features, because the reactivity of the metal center is finely modulated by a complex interplay of interactions within the protein matrix.

Enhancement of Peroxidase Activity in Artificial Mimochrome VI Catalysts through Rational Design.

Rational design provides an attractive strategy to tune and control the reactivity of bioinspired catalysts. Although there has been considerable progress in the design of heme oxidase mimetics with active-site environments of ever-growing complexity and catalytic efficiency, their stability during turnover is still an open challenge. Herein, we show that the simple incorporation of two 2-aminoisobutyric acids into an artificial peptide-based peroxidase results in a new catalyst (Fe -MC6*a) with higher resistance against oxidative damage and higher catalytic efficiency.