Advances in protein chemistry and structural biology最新文献

The emergence of antibiotic-resistant pathogens mostly due to intensive antibiotic use greatly endangers human health. For this reason, it has become necessary to search for new drugs or alternative treatments that are effective on resistant microorganisms. This review examines antimicrobial peptides (AMPs) which are part of the first primitive defense mechanism used by both eukaryotic and prokaryotic cells against many pathogens. AMPs are usually small (up to 50 amino acids), cationic peptides which make them bind to negatively charged cell membranes of pathogens for permeabilization and destruction. AMPs can act on antibiotic-resistant pathogens such as Enterococcus faecium, methicillin-resistant Staphylococcus aureus (MRSA), and Pseudomonas aeruginosa, and they offer unique advantages due to their membrane-active antimicrobial mechanisms that reduce the likelihood of developing resistance. AMPs have high therapeutic potential due to their broad-spectrum activities, and different mechanisms of action compared to traditional antibiotics. However, their practical application is often hampered by their limited activity, host toxicity and poor stability. To overcome these limitations, natural AMP sequences can be improved by protein engineering approaches. Surface display technology is one of the leading high-throughput protein engineering strategies where primary/secondary structures of AMPs can be modified and screened for various improvements. This review focuses on the key properties of antimicrobial peptides, as well as insights on the use of in vitro surface display techniques to develop next-generation AMPs for therapeutic uses.

Antimicrobial peptides (AMPs), which can be derived from diverse biological sources, exhibit a broad spectrum of inhibitory activity against bacteria, fungi, parasites, and viruses, positioning them as promising alternatives to traditional antibiotics. This review offers a comprehensive and systematic overview of the AMP research, encompassing their origins, classification, and mechanisms of action, with a focus on the application of AMPs in food preservation and the emerging role of artificial intelligence in the identification and design of novel AMPs.

Alzheimer's disease is a most prevalent type of dementia in elderly people. Extracellular accumulation of Amyloid-β (Aβ) and intracellular aggregation of Tau NFTs in the brain is proposed to be a key factor in the development of Alzheimer's disease. A fast-growing body of evidence strengthened the infectious hypothesis of sporadic type of AD. Recent clinical studies focused on the characterizing of antimicrobial peptides (AMPs), because it has been documented that some pathogenic microorganism, such as herpesviruses and particular bacterial strains, are generally present in AD individuals. And also, the environmental factors, such as persistent bacterial or viral infections, change the blood-brain barrier's (BBB) permeability, making it easier for opportunistic pathogens to colonise the brain. This review highlights the potential role of Aβ, which perform antimicrobial activity against diverse pathogens, significantly encouraging its role in the innate immune response. While mammalian amyloid is linked with disease, numerous microbes form amyloid fibrils to embattle the biofilm that prevent the cells from the surrounding environment. According to the microbial AD hypothesis, Aβ clumps up to combat the microbial infection.

Leptospirosis, caused by Leptospira bacteria, poses a significant global health threat with notable mortality rates. This study employs advanced transcriptomics to explore the complex interactions between host and pathogen, focusing on antimicrobial peptides (AMPs). Genomic data from mice infected with various Leptospira serotypes underwent rigorous quality control, alignment to the Mus musculus genome, and quantification using FeatureCounts. DESeq2 analysis revealed 491 differentially expressed genes (DEGs), shedding light on key molecular pathways crucial to leptospirosis pathogenesis, particularly involving AMP resistance mechanisms. Important molecular functions, KEGG pathways, cellular components, and biological processes linked to AMP resistance were revealed by functional enrichment analysis. These findings underscore roles in stress responses, immune modulation, and stimulus regulation. Utilizing Cytoscape, a protein-protein interaction network identified pivotal hub proteins such as Ptprc, Stat3, Syk, Stat5a, Stat1, Il18, Fcgr3, Jak2, Sell, and Jak1, integral to immune responses, signaling cascades, and cellular processes essential for AMP resistance. This comprehensive analysis provides valuable insights into the mechanisms underlying AMP resistance in leptospirosis. The identified biomarkers hold promise for developing targeted diagnostic tools and therapeutic strategies to combat AMP-resistant leptospirosis strains, potentially alleviating its global health impact. Further validation and comprehensive exploration are crucial to advancing our understanding and enhancing patient care strategies against antimicrobial resistance in leptospirosis.

Antimicrobial peptides (AMPs) constitute a promising class of next-generation therapeutics, exhibiting broad-spectrum efficacy and a diminished propensity for inducing resistance. Recent strides in computational biology have facilitated the rational design and high-throughput screening of AMPs tailored to target specific resistance mechanisms. In this study, we employed a structure-guided computational pipeline to identify and prioritize AMPs with inhibitory potential against OXA-51 β-lactamase, a pivotal enzyme contributing to carbapenem resistance in Acinetobacter baumannii. A comprehensive dataset comprising 300 AMPs, 250 of natural origin, and 50 synthetically engineered was curated through meta-analytical approaches. These peptides were systematically filtered based on key parameters, including physicochemical attributes, predicted toxicity, proteolytic stability, and aqueous solubility. Subsequent molecular docking analyses enabled the identification of eight high-affinity candidates, with AMP219 (NRC12), emerging as the top performer, exhibiting a binding energy of -214.98 kcal/mol. To further validate the binding stability and dynamic behavior of the AMP219 with the OXA-51 complex, a 300-nanosecond molecular dynamics simulation (MDS) was conducted. The results revealed sustained intermolecular interactions, persistent hydrogen bonding, and notable conformational rearrangements within the enzyme's active site, underscoring the peptide's inhibitory potential. Collectively, these findings emphasize the utility of integrative computational strategies in accelerating peptide-based drug discovery and provide a robust foundation for subsequent experimental validation against multidrug-resistant pathogens.

The rapid rise of antibiotic-resistant bacteria has become a major clinical challenge, creating an urgent need for alternative therapeutic strategies. Antimicrobial peptides (AMPs) have emerged as promising candidates in the fight against these resistant pathogens. Naturally produced by a wide variety of organisms, AMPs are a crucial part of the innate immune system, offering a broad-spectrum antimicrobial effect against bacteria, fungi, viruses, and parasites. Unlike traditional antibiotics, AMPs primarily target microbial membranes, which reduces the likelihood of resistance development. Beyond their pathogen-destroying properties, AMPs enhance immune responses, aid in wound healing, and exhibit anticancer properties. Their ability to act swiftly and in synergy with the host immune system offers a distinct advantage over conventional antibiotics. Furthermore, AMPs hold the potential to be developed into novel treatments for infections that have become resistant to all available therapies. However, bacterial resistance mechanisms to AMPs-such as membrane modifications, protease production, and biofilm formation-underscore the complex interactions between hosts and pathogens. Despite these challenges, AMPs present an exciting avenue across multiple sectors, including medicine, agriculture, and food safety. Recent research also highlights their potential in treating viral infections, including COVID-19, showcasing their versatile applications. This chapter discusses the role of AMPs in addressing antibiotic resistance, their mechanisms of action, and their diverse therapeutic applications beyond bacterial infections.

Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), constitute a class of endogenous oligopeptides that are integral to the innate immune system. These peptides exhibit potent and broad-spectrum antimicrobial activity, targeting a diverse array of pathogens, including Gram-positive and Gram-negative bacteria, enveloped and non-enveloped viruses, fungi, and select protozoan species. In addition to their immunological relevance, AMPs are increasingly recognized as promising candidates for next-generation therapeutics, particularly in the context of the escalating antimicrobial resistance (AMR) crisis. Their multifaceted mechanisms of action and molecular specificity position them as key candidates for biomedical research and pharmaceutical advancement. This comprehensive review delineates the current landscape of AMP research, emphasizing recent advances in structural classification, mechanistic elucidation, and therapeutic development. Special emphasis is given to the proliferation of AMP-centric bioinformatics repositories and algorithmic platforms that leverage machine learning (ML) and deep learning (DL) architectures to enable high-throughput peptide mining, rational design, functional annotation, and optimization. The integration of computational modeling with experimental pipelines such as molecular docking, atomistic simulations, and free energy perturbation analyses has significantly enhanced the resolution of peptide-protein interaction studies, facilitating predictive modeling at sub-nanometer scales. Clinical translational barriers are critically assessed, with a focus on emergent strategies that enhance pharmacokinetic stability, target specificity, and immunocompatibility of AMP-based formulations. Moreover, the review explores frontier technologies, including quantum-enhanced computing, adaptive algorithmic evolution, and deterministic sampling paradigms that are redefining the computational efficiency and design fidelity of peptide engineering workflows. Overall, this review underscores the transformative impact of advanced technological innovations in accelerating peptide discovery and bridging the gap between laboratory research and clinical practice.

Antimicrobial resistance (AMR) undermines the effectiveness of antibiotic treatment, and due to this, it now worldwide health concern. In general, antibiotics are used to control or combat bacteria, their widespread and irresponsible has contributed to the development bacterial resistance to some microbial drug. Due to this, treating patients identified with resistant bacteria is burdensome and, expensive, and success rates are low. Among the more successful tools are host defense peptides (HDPs), which represent a beneficial alternative due to their unique mechanisms of action and low toxicity toward host cells. HDPs are crucial innate immune system components, exhibiting antibacterial, antifungal, antiviral, and anti-inflammatory activities. Some peptides, such as human cathelicidin LL-37, exhibit direct pathogen-killing activity and the ability to modulate innate immune responses. HDPs also interact with various pattern recognition receptors (PRRs), such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), and C-type lectin receptors (CLRs), influencing downstream pathways essential for microbial clearance and inflammation regulation. These interactions damage the microbial membrane, stimulating cytokine production and immune cell recruitment. Furthermore, HDPs can modulate chemokine receptor signaling to coordinate leukocyte migration and enhance host protection. Despite these promising aspects, there are challenges to overcome, such as potential immunotoxicity, proteolytic instability, and low receptor specificity, which hinder clinical application. This review highlights the complex interaction between HDPs and immune receptors, which can be used to overcome AMR and inform next-generation anti-infective therapy development.

Antimicrobial peptides (AMPs) are tiny proteins essential for innate immunity in various taxa, including mammals and insects. They provide defence against a wide range of pathogens, including bacteria, viruses, fungi, and parasites. Apart from their antimicrobial properties, new studies have revealed the roles of AMPs in brain ageing, neurodegeneration, and neuroinflammation. With an emphasis on their dysregulation in glial and neuronal tissues and their role in neuroinflammation, mitochondrial dysfunction, and neuronal loss, we reviewed the new function of AMPs beyond their antimicrobial activity. Findings from Drosophila models of Huntington's disease, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and Ataxia-telangiectasia show that immune pathways, like Toll and immune deficiency, drive persistent or ectopic AMP expression, which is similar to the inflammatory processes seen in human neurodegenerative diseases. Furthermore, the dual function of AMPs as mediators of sterile inflammation and protective immunological agents reveals a universal paradox. The translational relevance of these findings is further supported by comparisons with human AMPs, such as LL-37 and β-defensins. LL-37 and β-defensins levels were found to be increased in the cerebrospinal fluid of patients suffering from meningitis. LL-37 is released from neurons and activates glial cells, boosting the production of inflammatory cytokines and decreasing neuronal survival. This chapter redefines AMPs as not only sentinels of microbial defence but also as important participants in preserving or disturbing brain homeostasis by establishing them as a link between immunity and neurobiology.

Alzheimer's disease is mainly caused by two proteins, Tau and Amyloid-β. While there are several cures currently being explored for it, there is no cure yet for the disease progression and prevention, but only those to alleviate the symptoms. One of the hypothesis for the cause of the Alzheimer's disease is the microbial hypothesis. This suggests that there are a lot of microorganisms present in our body which can contribute to the disease pathology by leading to symptoms such as neuroinflammation. Our body has certain molecules to maintain innate immunity, known as antimicrobial peptides. Recently, several studies suggest the roles of these molecules in the Alzheimer's disease as therapeutic molecules and as biomarkers. Amyloid beta which is one of the major proteins is suggested to be an antimicrobial peptide on its own. The formation of its oligomers and plaques is due to neuroprotective reasons. A similar theory exists for the formation of neurofibrillary tangles (NFTs) from Tau. There include lactoferrin, LL-37 and defensins. They are often found in association with the aggregated proteins, amyloid beta and Tau. Additionally, fluctuations in their levels are often observed in several fluids and regions inside in patients with AD compared to the control cohorts. While their therapeutic potential has been proven, their mechanisms of action, effectivity and expedition towards clinical studies is yet to be done.