Blockade of TMPRSS2-mediated priming of SARS-CoV-2 by the N-terminal peptide of lactoferrin

In addition to vaccines, there is an urgent need for supplemental antiviral therapeutics to dampen the persistent COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The transmembrane protease serine 2 (TMPRSS2), which is responsible for the proteolytic processing of the SARS-CoV-2 spike protein as virus priming for cell entry, appears as a rational therapeutic target for the clearance of SARS-CoV-2 infection. Accordingly, selective inhibitors of TMPRSS2 represent potential tools for prevention and treatment of COVID-19. Here, we tested the inhibitory capacities of the human milk glycoprotein lactoferrin and its N-terminal peptide pLF1, which we identified as inhibitors of plasminogen, a serine protease homologous to TMPRSS2. In vitro proteolysis assays revealed that, unlike full-length lactoferrin, pLF1 significantly inhibited the proteolytic activity of TMPRSS2. pLF1 inhibited both the proteolytic processing of the SARS-CoV-2 spike protein and the SARS-CoV-2 infection of simian Vero cells. Because lactoferrin is a natural product and several biologically active peptides, such as the N-terminally derived lactoferricins, are produced naturally by pepsin-mediated digestion, natural or synthetic peptides from lactoferrin represent well-achievable candidates for supporting prevention and treatment of COVID-19.

Bradykinin, as a Reprogramming Factor, Induces Transdifferentiation of Brain Astrocytes into Neuron-Like Cells

Kinins are endogenous, biologically active peptides released into the plasma and tissues via the kallikrein-kinin system in several pathophysiological events. Among kinins, bradykinin (BK) is widely distributed in the periphery and brain. Several studies on the neuro-modulatory actions of BK by the B2BK receptor (B2BKR) indicate that this neuropeptide also functions during neural fate determination. Previously, BK has been shown to induce differentiation of nerve-related stem cells into neuron cells, but the response in mature brain astrocytes is unknown. Herein, we used rat brain astrocyte (RBA) to investigate the effect of BK on cell transdifferentiation into a neuron-like cell morphology. Moreover, the signaling mechanisms were explored by zymographic, RT-PCR, Western blot, and immunofluorescence staining analyses. We first observed that BK induced RBA transdifferentiation into neuron-like cells. Subsequently, we demonstrated that BK-induced RBA transdifferentiation is mediated through B2BKR, PKC-δ, ERK1/2, and MMP-9. Finally, we found that BK downregulated the astrocytic marker glial fibrillary acidic protein (GFAP) and upregulated the neuronal marker neuron-specific enolase (NSE) via the B2BKR/PKC-δ/ERK pathway in the event. Therefore, BK may be a reprogramming factor promoting brain astrocytic transdifferentiation into a neuron-like cell, including downregulation of GFAP and upregulation of NSE and MMP-9 via the B2BKR/PKC-δ/ERK cascade. Here, we also confirmed the transdifferentiative event by observing the upregulated neuronal nuclear protein (NeuN). However, the electrophysiological properties of the cells after BK treatment should be investigated in the future to confirm their phenotype.

Marine Organisms as a Rich Source of Biologically Active Peptides

Oceanic environments are one of the largest sources of bioactive molecules, due to the high degree of biodiversity and the innumerable ecological relationships established between macro and microorganisms found in the different ecosystems of these complex environments. Marine organisms are being studied increasingly because they are considered important producers of biologically active peptides. Peptides extracted from marine sources have different functions and structures, when compared to peptides isolated from terrestrial sources, considering the different adaptive pressures undergone by these organisms throughout the evolutionary process. Most bioactive compounds isolated from marine environments are obtained from symbiont microorganisms. Of these microorganisms, bacteria are an important source of bioactive peptides, isolated by metagenomic studies from complex gene networks expressed under marine conditions. Several peptides have been shown to have biotechnological properties such as antimicrobial, antitumor, antihypertensive, anticoagulant, anti-fouling, and antioxidant activity and can be used in the pharmaceutical and food industries. This review article aims to provide an overview of peptides of biotechnological importance, isolated from different phyla of marine organisms, examining the relationship between structure and function of some of these peptides, as well as the ways of extracting, purifying and prospecting new peptides by traditional methods of isolation or sequence analysis in databases. It also intends to list the peptides that are already being produced and used by the industry, in its various branches, and their current state in the market and in clinical tests.

Biochemical and biophysical investigation of the HalM2 lanthipeptide synthetase using mass spectrometry

The rapid emergence of antimicrobial resistance in clinical settings has called for renewed efforts to discover and develop new antimicrobial compounds. Lanthipeptides present a promising, genetically-encoded molecular scaffold for the engineering of structurally complex, biologically active peptides. These peptide natural products are constructed by enzymes (lanthipeptide synthetases) with relaxed substrate specificity that iteratively modify the precursor lanthipeptide to generate structures with defined sets of thioether macrocycles. The mechanistic features that guide the maturation of lanthipeptides into their proper, fully-modified forms are obscured by the complexity of the multistep maturation, and the large size and dynamic structures of the synthetases and precursor peptides. Over the past several years, our lab has been developing a suite of mass spectrometry-based techniques that are ideally suited to untangling the complex reaction sequences and molecular interactions that define lanthipeptide biosynthesis. This review focuses on our development and application of these MS-based techniques to investigate the biochemical, kinetic, and biophysical properties of the haloduracin  class II lanthipeptide synthetase, HalM2.

A NOVEL PEPTIDE MODULATOR OF THE HUMAN CHANNEL NAV1.5 FROM LATRODECTUS TREDECIMGUTTATUS SPIDER VENOM

Spider venom contains a wide repertoire of pharmacologically active compounds, and in the case of some spider species bite, toxins from spider venom can play a fatal role for humans as well as other organisms. Among all the spiders, one could say the bite of Latrodectus tredecimguttatus, known as Black Widow spider, is very dangerous and can even lead to tragic consequences. Especially, voltage-gated sodium channels are responsible for propagating action potentials in excitable cells. NaV1.5 plays a crucial role in the human cardiac muscle, where it enhances the influx of sodium ions via the cell membrane, causing the fast depolarization phase of the cardiac action potential. It is also an important therapeutic target for heart disorders. Various venom-derived peptides have been observed as potential modulators of sodium channels, and these biologically active peptides are an abundant source for pharmacological tools.