Explore the vast range of titles available.

SARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α 1 -antitrypsin (α 1 AT), a highly abundant circulating serine protease inhibitor. Here, we report that α 1 AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α 1 AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α 1 AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α 1 AT-containing drugs has prospects for the therapy of COVID-19. Here, via screening of a polypeptide library from bronchoalveolar lavage, the authors identify and characterize α 1 -antitrypsin (α 1 AT) as SARS-CoV-2 inhibitor and show that α 1 AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion.

Marine invertebrates are a prime source of biologically active peptides due to their role in humoral immunity. These peptides typically exhibit broad-spectrum functions, including antibacterial, antifungal, anticancer, and immunomodulatory activities. In this report, we describe the identification and biological characterization of five novel bioactive peptides from the marine mollusk Pisania pusio. An extract of P. pusio was analyzed using nanoLC-ESI-MS-MS, and five peptides (PP1–5) were selected via bioinformatic screening as potential antimicrobial and anticancer peptides and subsequently validated experimentally. Among these, PP1, PP2, and PP4 were identified as cryptides derived from the proteolytic cleavage of actin, while PP3 and PP5 are novel peptides with no known protein precursors. All peptides exhibited moderate activity against Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, and Klebsiella pneumoniae with minimum inhibitory concentrations (MICs) predominantly at 100 µM. In contrast, only PP1 and PP5 were active against cancer cells, with PP1 being the most effective against A375 melanoma cells (IC50 = 17.08 µM). This experimental validation confirmed the utility of the integrated in silico/peptidomic pipeline for lead identification. None of these peptides showed significant hemolytic activity or toxicity on fetal lung fibroblasts over 800 μM, demonstrating promising in vitro selectivity. These results highlight the multifunctional nature of P. pusio-derived peptides and their potential as lead compounds for further optimization and development into therapeutic agents against microbial infections and cancer, subject to more comprehensive safety evaluations in relevant models

Nowadays, healthcare systems face two global challenges: the rise of multidrug-resistant pathogens and the growing incidence of cancer. Due to their broad spectrum of activities, antimicrobial peptides emerged as potential alternatives against both threats. Our group previously described the antifungal activity of the α-helical peptide Cm-p5, a derivative of the natural peptide Cm-p1, isolated from the coastal mollusk Cenchritis muricatus; however, its anti-cancer properties remained unexplored. Analyses through calorimetry and molecular dynamics simulations suggest the relevance of phosphatidylserine for the attachment of Cm-p5 to cancer cell membranes. Cm-p5 exhibited cytotoxic activity in a dose-dependent manner against A375 melanoma cells, without toxicity against non-malignant cells or hemolytic activity. DAPI/PI and DiSC3(5) staining confirmed permeabilization, disruption, and depolarization of A375 cytoplasmic membranes by Cm-p5. Furthermore, Annexin V-FITC/PI assay revealed the induction of cellular death in melanoma cells, which can result from the cumulative membrane damage and oxidative stress due to the overproduction of reactive oxygen species (ROS). Moreover, after the treatment, the proliferation of A375 cells was dampened for several days, suggesting that Cm-p5 might inhibit the recurrence of melanomas. These findings highlight the multifunctional nature of Cm-p5 and its potential for treating malignant melanoma.

The World Health Organization (WHO) prioritized 19 fungal species based on the significant impact of these pathogens on human health, including the emergence of antifungal resistance, which highlights the necessity of finding new antifungal therapies. Among these novel therapeutic approaches, the antimicrobial pore-forming peptide C14R has shown to be promising against Candida albicans and Candida auris. In this study, the antifungal in vitro efficacy of C14R was assessed against six additional species from the WHO priority list, Cryptococcus neoformans, Cryptococcus gattii, Candida glabrata, Candida tropicalis, Candida parapsilosis and Candida krusei, as well as against Candida dubliniensis. This study shows that C14R has good antifungal activity against several clinical isolates of the studied species, with MIC values between 0.8476 and 10.88 µg/mL. Most notably, some of the studied isolates are resistant to commonly used antifungal drugs but are susceptible to the peptide. C14R showed, moreover, its capacity to disrupt Cryptococcus capsules, beyond its already proven capacity to disrupt plasma membranes, and its antifungal activity was not affected depending on the serotype or species assessed. The inclusion of basidiomycete and ascomycete yeasts allowed us to display the broad-spectrum potential of C14R, highlighting it as a promising candidate as an antifungal agent.

The global rise in antimicrobial resistance among the ESKAPE pathogens represents a major challenge to public health. Here, we report the broad-spectrum antibacterial activity of the synthetic antimicrobial and pore-forming peptide C14R against all six ESKAPE species. Using a radial diffusion assay and resazurin-based viability testing, C14R exhibited a potent bactericidal effect with minimum inhibitory concentrations (MICs), defined as the lowest concentration of an antimicrobial agent that completely inhibits visible growth of planktonic microorganisms, ranging from 3.4 µg/mL (Enterococcus faecium, vancomycin-resistant) to 45.2 µg/mL (Klebsiella quasipneumoniae, ESBL). C14R also inhibited biofilm formation by Gram-positive pathogens, with minimum biofilm inhibitory concentrations (MBICs), referring to the minimal concentration required to prevent the development of biofilms, of 15.0 µg/mL (Staphylococcus aureus, MRSA) and 22.0 µg/mL (E. faecium, VRE), whereas Gram-negative biofilms showed higher tolerance. Together, these findings demonstrate that C14R retains high activity against multidrug-resistant ESKAPE strains, highlighting its potential as a lead compound for the development of next-generation antimicrobial drugs to expand the portfolio of available antibiotics and brace health systems against emerging severe infections.

Clostridioides (C.) difficile is a spore-forming, toxin-producing nosocomial human gut pathogen and a causative agent of gastrointestinal infections, leading to mild to severe diarrhea. Severe C. difficile infections (CDI) can cause life-threatening conditions, such as pseudomembranous colitis, colonic perforation, or toxic megacolon. The main virulence factors of C. difficile and responsible for CDI symptoms are two AB-type protein toxins, toxin A (TcdA) and toxin B (TcdB). TcdA and TcdB are large, single-chain proteins with multiple domains and glucosyltransferase activity. After receptor-mediated endocytosis, acidification of endosomes triggers insertion and pore formation of the toxins into the endosomal membrane for the delivery of their toxic glucosyltransferase domain (GTD) into the cytosol. There, the GTD glucosylates its target proteins, small GTPases of the Rho and/or Ras family, which leads amongst others to the collapse of the actin cytoskeleton and eventually to cell death. Here, we describe in silico predicted antimicrobial peptides, denoted as Angies, since they derive from the human endogenous protein angiogenin, as inhibitors for TcdA and TcdB. The strongest inhibitory capacity provided the derivative Angie 5, consistently in HeLa and Vero cells, as well as in the physiologically more relevant colon carcinoma cell line CaCo-2. Angie 5 delayed TcdA/TcdB-mediated glucosylation of its substrate proteins and, consequently, toxin-induced cell rounding as a consequence of actin-depolymerization. Moreover, the same Angie peptides that neutralized TcdA/TcdB also prevented the growth of C. difficile in vitro. In conclusion, our study paves the way for the development of antimicrobial peptide-based anti-toxin strategies to address C. difficile -associated diseases (CDADs).

Background/Objectives: Infections caused by Candida albicans, Candidozyma auris, and Candida parapsilosis increasingly challenge current treatment options as resistance to currently used antifungals is continuously developing. Neutralizing antimicrobial peptides (nAMPs), which modulate pathogenic behavior rather than inducing cell death, represent a promising approach to fighting against fungal infections. Methods: This study established a whole-cell phage display workflow to identify novel nAMPs, and therefore three independent biopanning processes with the Ph.D.-12 phage display library against C. albicans, C. auris, and C. parapsilosis cells were conducted. Results: Phage display produced species-selective, high-affinity peptides that were non-cytotoxic to human cells and did not affect planktonic Candida viability. These peptides inhibited early biofilm formation, and several also slowed early biofilm maturation down. Conclusions: These findings demonstrate that whole-cell phage display as a powerful and adaptable discovery tool is suitable for identifying nAMPs that neutralize biofilm development without toxicity towards human cells. Beyond the peptides described here, this approach expands the methodological toolbox for antifungal research and provides a sustainable approach for generating targeted peptides.

Unlike other human biological fluids, semen contains multiple types of amyloid fibrils in the absence of disease. These fibrils enhance HIV infection by promoting viral fusion to cellular targets, but their natural function remained unknown. The similarities shared between HIV fusion to host cell and sperm fusion to oocyte led us to examine whether these fibrils promote fertilization. Surprisingly, the fibrils inhibited fertilization by immobilizing sperm. Interestingly, however, this immobilization facilitated uptake and clearance of sperm by macrophages, which are known to infiltrate the female reproductive tract (FRT) following semen exposure. In the presence of semen fibrils, damaged and apoptotic sperm were more rapidly phagocytosed than healthy ones, suggesting that deposition of semen fibrils in the lower FRT facilitates clearance of poor-quality sperm. Our findings suggest that amyloid fibrils in semen may play a role in reproduction by participating in sperm selection and facilitating the rapid removal of sperm antigens. Seminal plasma, the fluid portion of semen, helps to transport sperm cells to the egg during sexual reproduction. Seminal plasma contains numerous proteins that help the sperm to survive and, in recent years, researchers discovered that it also harbours protein deposits known as amyloid fibrils. Such protein deposits are generally associated with neurodegenerative diseases such as Alzheimer's and Parkinson’s disease, where a build-up of fibrils can damage the nervous system. Semen amyloids, however, are present in the absence of disease, but can boost infection by HIV and other sexually transmitted viruses, by shuttling virus particles to their target cells. Despite these damaging effects, some researchers had suggested that amyloids in semen could be beneficial for humans, though it was unclear what these benefits might be. Roan et al. now set out to assess how semen amyloids affect human sperm activity. The results show that semen amyloids bind to damaged sperm cells and immobilize them, which are then quickly cleared away by immune cells. This could ensure that only the fittest sperm cells reach the egg. These findings suggest that amyloids can potentially serve beneficial roles for reproduction. A next step will be to investigate how semen amyloids trap unwanted sperm and how immune cells know when to remove it. More research is needed to investigate if problems in these processes could lead to infertility in men.

Antimicrobial peptides (AMPs) are widespread in multicellular organisms. These structurally diverse molecules are produced as the first line of defense against pathogens such as bacteria, viruses, fungi, and parasites. Also known as host defense peptides in higher eukaryotic organisms, AMPs display immunomodulatory and anticancer activities. During the last 30 years, technological advances have boosted the research on antimicrobial peptides, which have also attracted great interest as an alternative to tackling the antimicrobial resistance scenario mainly provoked by some bacterial and fungal pathogens. However, the introduction of natural AMPs in clinical trials faces challenges such as proteolytic digestion, short half-lives, and cytotoxicity upon systemic and oral application. Therefore, some strategies have been implemented to improve the properties of AMPs aiming to be used as effective therapeutic agents. In the present review, we summarize the discovery path of AMPs, focusing on preclinical development, recent advances in chemical optimization and peptide delivery systems, and their introduction into the market.

Expanding the antifungal drug arsenal for treating Candida infections is crucial in this era of the rising life expectancy of patients with immunosuppression and comorbidities. Infections caused by Candida species are on the rise, including those caused by multidrug-resistant strains or species, and the list of antifungals approved for the treatment of these infections is still limited. Antimicrobial peptides (AMPs) are short cationic polypeptides whose antimicrobial activity is under intense investigation. In this review, we present a comprehensive summary of the AMPs with anti-Candida activity that have undergone successful preclinical or clinical trials. Their source, mode of action, and animal model of infection (or clinical trial) are presented. In addition, as some of these AMPs have been tested in combination therapy, the advantages of this approach, as well as the studied cases that have used AMPs and other drugs concomitantly to fight Candida infections, are described.