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Developing greener synthetic methodologies requires replacing hazardous reagents with more sustainable alternatives. In solid-phase peptide synthesis (SPPS), piperidine is the standard base for Fmoc group removal, but its toxicity, environmental concerns, and regulatory restrictions have prompted the search for safer substitutes. This study evaluates various green bases based on their GSK greenness score and chemical-physical properties similar to piperidine. Their performance was assessed through deprotection kinetics tests in different green solvents, followed by efficiency evaluations in solid-phase synthesis. Among the tested bases, DBN demonstrated the highest efficiency, achieving rapid Fmoc removal at the lowest concentration across all green solvents. Additionally, DBN effectively minimized side reactions such as racemization, particularly in Anisole/NOP (75:25). Finally, DBN was tested in the synthesis of a model peptides, yielding comparable results to piperidine. These findings highlight DBN as a promising green alternative for SPPS, contributing to the advancement of more sustainable peptide synthesis strategies.

In recent years, peptides have gained more success as therapeutic compounds. Nowadays, the preferred method to obtain peptides is solid-phase peptide synthesis (SPPS), which does not respect the principles of green chemistry due to the large number of toxic reagents and solvents used. The aim of this work was to research and study an environmentally sustainable solvent able to replace dimethylformamide (DMF) in fluorenyl methoxycarbonyl (Fmoc) solid-phase peptide synthesis. Herein, we report the use of dipropyleneglycol dimethylether (DMM), a well-known green solvent with low human toxicity following oral, inhalant, and dermal exposure and that is easily biodegradable. Some tests were needed to evaluate its applicability to all the steps of SPPS, such as amino acid solubility, resin swelling, deprotection kinetics, and coupling tests. Once the best green protocol was established, it was applied to the synthesis of different length peptides to study some of the fundamental parameters of green chemistry, such as PMI (process mass intensity) and the recycling of solvent. It was revealed that DMM is a valuable alternative to DMF in all steps of solid-phase peptide synthesis.

Mycalin A (MA) is a polybrominated C-15 acetogenin isolated from the marine sponge Mycale rotalis. Since this substance displays a strong antiproliferative bioactivity towards some tumour cells, we have now directed our studies towards the elucidation of the MA interactome through functional proteomic approaches, (DARTS and t-LIP-MS). DARTS experiments were performed on Hela cell lysates with the purpose of identifying MA main target protein(s); t-LiP-MS was then applied for an in-depth investigation of the MA–target protein interaction. Both these techniques exploit limited proteolysis coupled with MS analysis. To corroborate LiP data, molecular docking studies were performed on the complexes. Finally, biological and SPR analysis were conducted to explore the effect of the binding. Mortalin (GRP75) was identified as the MA’s main interactor. This protein belongs to the Hsp70 family and has garnered significant attention due to its involvement in certain forms of cancer. Specifically, its overexpression in cancer cells appears to hinder the pro-apoptotic function of p53, one of its client proteins, because it becomes sequestered in the cytoplasm. Our research, therefore, has been focused on the possibility that MA might prevent this sequestration, promoting the re-localization of p53 to the nucleus and facilitating the apoptosis of tumor cells.

Bovine lactoferrin is a biglobular multifunctional iron binding glycoprotein that plays an important role in innate immunity against infections. We have previously demonstrated that selected peptides from bovine lactoferrin C-lobe are able to prevent both Influenza virus hemagglutination and cell infection. To deeper investigate the ability of lactoferrin derived peptides to inhibit Influenza virus infection, in this study we identified new bovine lactoferrin C-lobe derived sequences and corresponding synthetic peptides were synthesized and assayed to check their ability to prevent viral hemagglutination and infection. We identified three tetrapeptides endowed with broad anti-Influenza activity and able to inhibit viral infection in a concentration range femto- to picomolar. Our data indicate that these peptides may constitute a non-toxic tool for potential applications as anti-Influenza therapeutics.

Influenza is a highly contagious, acute respiratory illness, which represents one of the main health issues worldwide. Even though some antivirals are available, the alarming increase in virus strains resistant to them highlights the need to find new drugs. Previously, Superti et al. deeply investigated the mechanism of the anti-influenza virus effect of bovine lactoferrin (bLf) and the role of its tryptic fragments (the N- and C-lobes) in antiviral activity. Recently, through a truncation library, we identified the tetrapeptides, Ac-SKHS-NH2 (1) and Ac-SLDC-NH2 (2), derived from bLf C-lobe fragment 418–429, which were able to bind hemagglutinin (HA) and inhibit cell infection in a concentration range of femto- to picomolar. Starting from these results, in this work, we initiated a systematic SAR study on the peptides mentioned above, through an alanine scanning approach. We carried out binding affinity measurements by microscale thermophoresis (MST) and surface plasmon resonance (SPR), as well as hemagglutination inhibition (HI) and virus neutralization (NT) assays on synthesized peptides. Computational studies were performed to identify possible ligand–HA interactions. Results obtained led to the identification of an interesting peptide endowed with broad anti-influenza activity and able to inhibit viral infection to a greater extent of reference peptide.

Background/Objectives: Viral respiratory infections have a significant impact on global health and the economy. While vaccines are effective in preventing infection, they might not be available or sufficient when used alone and must be complemented by specific therapeutic strategies. The development of new antiviral agents is increasingly important due to the continual emergence of novel respiratory pathogens. Previously we identified bovine lactoferrin (bLf)-derived tetrapeptides and peptidomimetics that showed potent in vitro activity against the influenza A virus in the picomolar range. Methods: Inspired by these results, in this study, we evaluated the antiviral potential of these compounds against HCoV-229E, a human coronavirus that can cause severe disease in immunocompromised individuals, using a compound repositioning approach. Results: Functional studies revealed that SK(N-Me)HS (3) interferes with viral entry and replication, while compound SNKHS (5) primarily blocks infection in the early stages. Biophysical analyses confirmed the occurrence of high-affinity binding to the viral spike protein, and computational studies suggested that the compounds target a region involved in conformational changes necessary for membrane fusion. Conclusions: These findings highlight these compounds as promising candidates for coronavirus entry inhibition and underscore the value of compound repurposing in antiviral development.

Among enhancing strategies proposed in ocular drug delivery, a rising interest is directed to cell penetrating peptides (CPPs), amino acid short sequences primarily known for their intrinsic ability to cell internalization and, by extension, to cross biological barriers. In fact, CPPs may be considered as carrier for delivering therapeutic agents across biological membranes, including ocular tissues. Several CPPs have been proposed in ophthalmic delivery, and, among them, penetratin (PNT), a 16-amino acids natural peptide, stands out. Therefore, we describe the synthesis via the mimotopic approach of short fluorescently labeled analogues of both PNT and its reversed sequence PNT-R. Their ability to cross ocular membranes was checked ex vivo using freshly explanted porcine cornea. Furthermore, some sequences were studied by circular dichroism. Despite the hydrophilic nature and the relatively high molecular weight (approx. 1.6 kDa), all analogues showed a not negligible trans-corneal diffusion, indicating a partial preservation of penetration activity, even if no sequences reached the noteworthy ability of PNT. It was not possible to find a correlation between structure and corneal penetration ability, and further studies, exploring peptides distribution within corneal layers, for example using imaging techniques, deserve to be performed to figure out a possible difference in intracellular delivery.

Influenza viruses represent a leading cause of high morbidity and mortality worldwide. Approaches for fighting flu are seasonal vaccines and some antiviral drugs. The development of the seasonal flu vaccine requires a great deal of effort, as careful studies are needed to select the strains to be included in each year’s vaccine. Antiviral drugs available against Influenza virus infections have certain limitations due to the increased resistance rate and negative side effects. The highly mutative nature of these viruses leads to the emergence of new antigenic variants, against which the urgent development of new approaches for antiviral therapy is needed. Among these approaches, one of the emerging new fields of “peptide-based therapies” against Influenza viruses is being explored and looks promising. This review describes the recent findings on the antiviral activity, mechanism of action and therapeutic capability of antiviral peptides that bind HA, NA, PB1, and M2 as a means of countering Influenza virus infection.

Effective therapy against the influenza virus is still an unmet goal. Drugs with antiviral effects exist, but the appearance of resistant viruses pushes towards the discovery of drugs with different mechanisms of action. New anti-influenza molecules should target a good candidate, as a new anti-influenza molecule could be an inhibitor of the influenza A virus hemagglutinin (HA), which plays a key role during the early phases of infection. In previous work, we identified two tetrapeptide sequences, SLDC (1) and SKHS (2), derived from bovine lactoferrin (bLf) C-lobe fragment 418–429, which were able to bind HA and inhibit cell infection at picomolar concentration. Considering the above, the aim of this study was to synthesize a new library of peptidomimetics active against the influenza virus. In order to test their ability to bind HA, we carried out a preliminary screening using biophysical assays such as surface plasmon resonance (SPR) and orthogonal immobilization-free microscale thermophoresis (MST). Biological and computational studies on the most interesting compounds were carried out. The methods applied allowed for the identification of a N-methyl peptide, S(N-Me)LDC, which, through high affinity binding of influenza virus hemagglutinin, was able to inhibit virus-induced hemagglutination and cell infection at picomolar concentration. This small sequence, with high activity, represents a good starting point for the design of new peptidomimetics and small molecules.

Redox signaling regulates different gastrointestinal (G.I.) epithelium functions. At the intestinal level, the loss of redox homeostasis in intestinal epithelial cells (IECs) is responsible for the pathogenesis and development of a wide diversity of G.I. disorders. Thus, the manipulation of oxidative stress in IECs could represent an important pharmacological target for different diseases. In this study, peptides released from in vitro gastro intestinal digestion of different buffalo-milk commercial dairy products were identified and evaluated for their bioactive properties. In particular, six G.I. digests of dairy products were tested in a model of oxidative stress for IECs. Among them, buffalo ricotta cheese was the most active and the presence of an abundant β-lactoglobulin peptide (YVEELKPTPEGDL, f:60-72) was also revealed. The antioxidant potential of the identified peptide was also evaluated in a model of hydrogen peroxide (H2O2)-induced oxidative stress in the IEC-6 cell line. The peptide was able to reduce ROS release, while, on the other hand, it increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation and the expression of antioxidant cytoprotective factors, such as heme oxygenase 1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO1), and superoxide dismutase (SOD). These results indicate that buffalo ricotta cheese-isolated peptide could have potential in the treatment of some gastrointestinal disorders.