ACS Bio & Med Chem Au最新文献

{"title":"Targeted Protein Degradation for Agricultural Applications: Rationale, Challenges, and Outlook.","authors":"Denis Fourches, Joseph Pilotte, Brian E Watts, Daniel J Saltzberg, Robert M Cicchillo","doi":"10.1021/acsbiomedchemau.5c00111","DOIUrl":"10.1021/acsbiomedchemau.5c00111","url":null,"abstract":"<p><p>Farmers urgently need novel technologies to ensure global food security for the rapidly expanding population, yet crop protection has seen little innovation in decades. Mounting regulatory pressures, pest resistance, and environmental concerns are driving demand for novel sustainable solutions. Beyond traditional small molecule active ingredients, very few alternative modalities (<i>e.g</i>., peptides, RNAi, biopesticides) have reached the market. Meanwhile, targeted protein degradation (TPD) has emerged as a breakthrough modality for human therapeutics, with numerous proteolysis-targeting chimeras (PROTACs) and molecular glues (MGs) advancing through clinical trials. Those compounds induce potent and selective degradation of protein targets via the ubiquitin-proteasome system (UPS). Recently, PROTACs have been shown to function in both insect cells and in whole insect organisms, marking a pivotal step toward their use as next-generation crop protection solutions. In this perspective, we showcase the rationale, key challenges, and potential breadth of applications of targeted protein degraders for agricultural purposes. The TPD technology is a promising and potentially disruptive alternative to traditional small molecule inhibitors in agriculture.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 5","pages":"778-791"},"PeriodicalIF":4.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145330123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Indole-2-carboxamides Optimization for Antiplasmodial Activity.","authors":"Malkeet Kumar, Anees Ahmad, Anna Caroline Campos Aguiar, Sarah El Chamy Maluf, Anwar Shamim, Mariana Ferrer, Guilherme E Souza, Marcos L Gazarini, Dhelio B Pereira, Thomas W von Geldern, Delphine Baud, Barry Jones, Susanta Kumar Mondal, Paul A Willis, Rafael Victorio Carvalho Guido, Luiz Carlos Dias","doi":"10.1021/acsbiomedchemau.5c00058","DOIUrl":"10.1021/acsbiomedchemau.5c00058","url":null,"abstract":"<p><p>Malaria still stands out as one of the most devastating and prevalent diseases globally, where the rise of resistance to different antimalarial drugs in different regions has posed significant obstacles to global treatment and elimination. Consequently, there is a pressing need for the development of new antimalarial agents with novel modes of action. In this study, we report the identification and optimization of new indole-2-carboxamide derivatives where structural modifications have yielded new compounds <b>6x</b> with enhanced potency (<i>Pf</i>3D7-IC50 ∼ 0.3 μM) and improved metabolic stability (hMics = 3 μL/min/mg), while also minimizing the human ether-a-go-go-related gene (hERG, IC₅₀ > 20 μM) channel activity and cytotoxic effect on hepatic cells (CC₅₀ > 30 μM). Mode-of-action investigations revealed that a representative compound from this series interfered with homeostasis of the parasite's digestive vacuole. However, cross-resistance was observed with resistant strains, which was linked to efflux pumps such as <i>Plasmodium falciparum</i> chloroquine resistance transporter (<i>Pf</i>CRT). Despite this challenge, these indole-2-carboxamides provide versatile molecular templates for innovative medicinal chemistry to overcome cross-resistance while maintaining other attractive properties of this novel series.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 5","pages":"821-839"},"PeriodicalIF":4.3,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531871/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145330109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thermodynamic Coupling between Folding Correctors and the First of Dimerized Nucleotide Binding Domains in CFTR","authors":"Guangyu Wang*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c00014","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00014","url":null,"abstract":"<p >The most common cystic fibrosis mutation is the F508del mutation in the human cystic fibrosis transmembrane conductance regulator (hCFTR), which causes misfolding of the first of two nucleotide binding domains (NBD1/2), preventing Mg/ATP-dependent NBD dimerization for normal function. Although folding correctors elexacaftor/VX-445 and lumacaftor/VX-809 have been combined to correct the NBD1 misfolding, the exact correction pathway is still unknown. In this study, the constrained tertiary noncovalent interaction networks or the thermoring structures of dimerized NBD1 in hCFTR/E1371Q with or without F508del were analyzed to identify the weakest noncovalent bridge as the final post-translational tertiary folding of dimerized NBD1 in response to folding correctors. These computational analyses suggested that hCFTR primarily used cooperative folding between α- and β-subdomains in dimerized NBD1 as the last step upon binding of the potentiator ivacaftor/VX-770. However, the binding of folding correctors allosterically protected the α-subdomain from misfolding until subsequent core formation. This thermodynamic protective mechanism, unlike the chaperone-based one in cotranslational NBD1 folding, may restore posttranslational NBD1 folding for tight Mg/ATP-mediated NBD dimerization in the F508del mutation and also potentially apply to treating other cystic fibrosis patients with rare mutations.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 4","pages":"593–601"},"PeriodicalIF":4.3,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsbiomedchemau.5c00014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selenium Exerts Antimicrobial Activity against the Perinatal Pathogen <i>Streptococcus agalactiae</i> and Perturbs Bacterial Interactions with Human Gestational Membranes.","authors":"Riya Chinni, Kensley Horner, Walter Avila, Shannon D Manning, Jennifer A Gaddy, Steven Damo","doi":"10.1021/acsbiomedchemau.5c00112","DOIUrl":"10.1021/acsbiomedchemau.5c00112","url":null,"abstract":"<p><p><i>Streptococcus agalactiae</i> also known as Group B <i>Streptococcus</i> (GBS) is a Gram-positive, encapsulated, pathogenic bacterium. GBS causes severe perinatal infections that lead to chorioamnionitis, funisitis, premature rupture of membranes, preterm birth, maternal sepsis, neonatal sepsis, stillbirth, and maternal demise. Epidemiological data indicate that the nutrient selenium provides protection against infection and adverse disease outcomes and is a critical nutrient for development of a healthy pregnancy. We hypothesized that selenium could have antimicrobial activity against GBS. To test this, we employed a panel of colonizing and invasive GBS strains and evaluated the bacterial growth in response to selenium exposure. Our results indicate that selenium can inhibit GBS growth and adherence to gestational tissues and that colonizing strains are more sensitive to selenium than invasive strains. Together, these results indicate that selenium could be deployed as a cost-effective intervention to ameliorate the risk of GBS perinatal infections.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 5","pages":"815-820"},"PeriodicalIF":4.3,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145330115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bridging Viral Glycobiology and Lectin Biotechnology for Antiviral and Diagnostic Strategies.","authors":"Benildo Sousa Cavada, Vinicius Jose Silva Osterne, Messias Vital Oliveira, Wandemberg Paiva Ferreira, Cornevile Correia Neto, Kyria Santiago Nascimento, Vanir Reis Pinto-Junior","doi":"10.1021/acsbiomedchemau.5c00115","DOIUrl":"10.1021/acsbiomedchemau.5c00115","url":null,"abstract":"<p><p>Lectins, proteins that reversibly bind specific glycan motifs, offer dual utility as molecular probes or inhibitors of virus-host interactions. This review explores the molecular interactions between lectins and viral envelope glycoproteins, emphasizing their applications as antiviral agents and diagnostic tools. Enveloped viruses, such as HIV, Influenza, Herpesviruses, and Coronaviruses, exhibit dense glycosylation on their surface proteins, forming a glycan shield rich in high-mannose and complex glycans crucial for viral processes and immune evasion. Lectins exploit these glycan shields by selectively targeting conserved glycosylation sites on key viral proteins like gp120 (HIV), hemagglutinin (Influenza), spike (SARS-CoV-2), and glycoprotein D (HSV), thereby interfering with viral entry. Potent inhibitory activity across diverse virus families has been demonstrated for natural lectins such as griffithsin (GRFT), cyanovirin (CV-N), and banana lectin (BanLec), with novel fungal and algal lectins continually expanding the list. Concurrently, lectin-based biosensors utilizing electrochemical, plasmonic, and microfluidic platforms, often enhanced by nanomaterials or aptamers, enable sensitive and specific detection of glycosylated viral targets. Despite challenges including potential immunogenicity and production scalability, ongoing bioengineering efforts aim to refine lectin specificity, reduce toxicity, and enhance overall functionality. These collective advances showcase the role of lectins as versatile molecular tools for the detection, inhibition, and mechanistic study of viral pathogens.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 5","pages":"792-814"},"PeriodicalIF":4.3,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12531872/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Functional <i>D</i>- and <i>L</i>‑Naphthalenediimide-Peptides: Microwave-Driven Synthesis, Supramolecular Aggregation, and Multiphoton Fluorescence Lifetime Imaging Microscopy in Living Cells.","authors":"Simone G Giuffrida, David G Calatayud, Fernando Cortezon-Tamarit, Haobo Ge, Vincenzo Mirabello, Dora-Maria Răsădean, Charareh Pourzand, Stanley W Botchway, Pedro Estrela, G Dan Pantoş, Ian M Eggleston, Sofia I Pascu","doi":"10.1021/acsbiomedchemau.5c00064","DOIUrl":"10.1021/acsbiomedchemau.5c00064","url":null,"abstract":"<p><p>We report the microwave-assisted synthesis of a novel family of peptide-linked optical imaging probes incorporating the <i>L</i>-[7,13] bombesin fragment (denoted <i>L</i>-[7,13]-BBN) as a functional building block currently used for targeting the gastrin-releasing peptide receptor (GRPR) in cancer cells. Given the importance of chirality in probe design, we synthesized and evaluated both <i>L</i>- and <i>D</i>-amino acid-substituted naphthalenediimide (NDI), namely, the monopeptide (<i>L</i>-<b>3</b>) and corresponding bis-peptide (<i>L</i>-<b>4</b>) conjugates. These bioconjugates were characterized using NMR, fluorescence spectroscopy, including excitation-emission mapping, and mass spectrometry, confirming their spectroscopic tunability, water solubility, and ability to form supramolecular aggregates. Aggregation behavior was demonstrated by scanning electron microscopy (SEM) and Time-Correlated Single-Photon Counting (TCSPC) spectroscopy, while circular dichroism studies revealed a stereochemistry-driven self-assembly influenced by 4-iodophenylalanine modifications. Additionally, a new, desymmetrized NDI-based bioconjugate (<i>L</i>-<b>6</b>), which incorporates the <i>L</i>-[7,13]-BBN fragment and a functional BODIPY fluorescent label, was synthesized in a stepwise manner via the microwave-assisted methods developed hereby. Cytotoxicity assays showed that these are benign, nontoxic probes at the time of imaging experiments and up to 72 h observation. Cellular uptake and localization properties of all compounds were assessed using confocal laser-scanning microscopy correlated with multiphoton fluorescence lifetime imaging microscopy (MP FLIM). This imaging method provided insights into the distinct behaviors of mono- vs bis-substituted peptide conjugates in live PC-3 prostate cancer cells, known to overexpress GRPR, and in A431 cells, known to overexpress the epidermal growth factor receptor (EGFR). Notably, the <i>L</i>- and <i>D</i>-stereochemistries of the BBN-[7,13] fragment played a crucial role in modulating the uptake and subcellular localization of bioconjugates of type 3 and 4 in lysosomes while the presence of the BODIPY unit additionally directed the biolocalization of compound <i>L</i>-<b>6</b> toward the endoplasmic reticulum of multiple cellular environments, including in living PC-3 and A431 cells. These findings are relevant for the design of new biologically active probes, including proteolysis-inactive, peptide conjugates for cancer biomarker detection and imaging.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 6","pages":"947-965"},"PeriodicalIF":4.3,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12715529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145805816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Kinetic Characterization of F420-Dependent Sugar-6-Phosphate Dehydrogenase from Cryptosporangium arvum","authors":"Alaa Aziz,&nbsp;Desiree R. Czapski,&nbsp;Ravi Ramkissoon,&nbsp;Md Sabid Ahamed,&nbsp;Sarah Al-Noubani,&nbsp;Andrew J. Mier,&nbsp;Oreoluwa Adeleke,&nbsp;Sharel Cornelius,&nbsp;Saiful Chowdhury,&nbsp;Frank W. Foss Jr,&nbsp;Joseph A. Buonomo,&nbsp;Ghader Bashiri and Kayunta L. Johnson-Winters*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c00085","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00085","url":null,"abstract":"<p ><i>F</i>₄₂₀-dependent glucose-6-phosphate dehydrogenase (FGD) catalyzes the oxidation of glucose-6-phosphate (G6P) to 6-phosphogluconolactone (6PG). Recent phylogenetic analyses have identified a new subclass of these enzymes, <i>F</i>₄₂₀-dependent sugar-6-phosphate dehydrogenases (FSDs), which act on a broader range of 6-phosphate sugars, including fructose-6-phosphate (F6P) and mannose-6-phosphate (M6P). One such enzyme from <i>Cryptosporangium arvum</i> (<i>Cryar</i>-FGD) was characterized by using binding assays and kinetic analyses, nuclear magnetic resonance (NMR), and mass spectrometry. Results showed strong binding affinities for all substrates. Steady-state kinetic analysis revealed that G6P has the highest catalytic efficiency, with a <i>k</i>_cat(app) of 6.4 ± 0.2 s^–1, compared to 1.4 ± 0.1 s^–1 for F6P and 0.32 ± 0.02 s^–1 for M6P. Pre steady-state spectral features for the G6P reaction resembled those of <i>Mycobacterium tuberculosis</i> FGD. While the F6P reaction displayed distinct spectral features, <i>F</i>₄₂₀ reduction was still observed. In contrast, the spectra for the M6P reaction were markedly different from those of G6P and F6P. Across all substrates, no catalytic intermediates were detected, and hydride transfer was not rate-limiting. As with G6P, the reaction with F6P also produced 6PG. Notably, NMR data showed that F6P was isomerized to G6P, suggesting isomerase activity. In contrast, M6P induced only spectral shifts with no evidence of isomerization or 6PG formation. However, mass spectrometry confirmed oxidized products for all three sugars, each with a mass of 299.0 ± 0.1. Collectively, these findings reveal that <i>Cryar</i>-FGD exhibits both dehydrogenase and isomerase activity, uncovering a newly identified dual enzymatic function and establishing its role as a multifunctional enzyme.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 4","pages":"726–737"},"PeriodicalIF":4.3,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsbiomedchemau.5c00085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward a Beautiful Amalgam: The Necessity of Heterogeneity in RNA Science and Research Culture","authors":"Sudeshi M. Abedeera,&nbsp;Mary Donnelly,&nbsp;James Hagerty,&nbsp;Shaila Kolli,&nbsp;Srinivasa R. Penumutchu,&nbsp;Louis G. Smith and Blanton S. Tolbert*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c00114","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00114","url":null,"abstract":"<p >RNA biology exemplifies functional heterogeneity─distinct RNA classes are expressed in tissue- and development-specific contexts, adopt dynamic conformational ensembles, and form intricate, context-dependent interactions with proteins and other molecules to regulate gene expression. These features make RNA a powerful metaphor for reimagining scientific culture. Just as RNA achieves biological complexity through versatility, feedback loops, and communication, research environments thrive when they support dynamic interactions, structural adaptability, and the intentional inclusion of divergent perspectives and experiences. However, unlike RNA, research culture is shaped by human behavior, institutional norms, and systemic barriers─forces that can suppress innovation and limit who contributes to scientific discovery. Scientific excellence demands the integration of wide-ranging perspectives to challenge paradigms and push boundaries. Yet entrenched structures often reward conformity and marginalize creativity born from difference. By embracing the principles inherent to RNA biology─contextual responsiveness, structural plasticity, and cooperativity─we can transform scientific culture into one that is more inclusive, welcoming, and adaptable. This perspective argues that the biological elegance of RNA offers more than molecular insight; it provides a conceptual framework for building research environments that harness the full spectrum of talent in our richly heterogeneous society, ultimately accelerating scientific progress and broadening its societal impact.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 4","pages":"519–530"},"PeriodicalIF":4.3,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsbiomedchemau.5c00114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Introducing the Tutorial Manuscript Type at the ACS Au Community Journals","authors":"Squire J. Booker,&nbsp;Stephanie L. Brock,&nbsp;Xiangdong Li,&nbsp;Géraldine Masson,&nbsp;Sébastien Perrier,&nbsp;Vivek V. Ranade,&nbsp;Raymond E. Schaak,&nbsp;Gemma C. Solomon and Shelley D. Minteer*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c00143","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00143","url":null,"abstract":"","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 4","pages":"484–485"},"PeriodicalIF":4.3,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsbiomedchemau.5c00143","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144862844","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poly-Arginine Tails and Helical Segments of Natural Antimicrobial Peptides Display Concerted Action at Membranes for Enhanced Antimicrobial Effects","authors":"Navleen Kaur,&nbsp;Kinjal Mondal,&nbsp;Megan E. Mitchell,&nbsp;Sarala Padi,&nbsp;Jeffery B. Klauda,&nbsp;Antonio Cardone,&nbsp;Frank Heinrich,&nbsp;Christina R. Harris,&nbsp;David K. Giles,&nbsp;Mary T. Rooney,&nbsp;Erik B. Watkins,&nbsp;Myriam L. Cotten,&nbsp;David P. Hoogerheide and Mihaela Mihailescu*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c00084","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00084","url":null,"abstract":"<p >Sequence motifs or patterns found in natural antimicrobial peptides (AMPs) have a great impact on their microbicidal activities. Here, through database inquiries and biological assays, we explore the enhanced antibacterial function associated with poly arginine (poly-R) motifs that typically occur as 3–5 concatenated R residues in many natural AMPs. Using a suite of biophysical techniques, we explore the structural consequences of a C-terminal poly-R motif at membranes and correlate our findings with the functional assays. We use natural peptides, such as Tilapia piscidin 4 (TP4), as an example of how various segments in an AMP play separate and synergistic roles to achieve unmatched bactericidal effects. The function of the poly-R segment is highly consequential since the simple addition of a five-arginine (R5) tail to an otherwise inert and weakly binding helical peptide creates a potent AMP. We investigate interactions of AMPs with lipid bilayers mimicking bacterial membrane compositions, including lipopolysaccharides, to show that the poly-R tail has a key role in initiating membrane destabilization through lipid segregation and water sequestration effects, all of which facilitate insertion and translocation of the amphipathic, α-helical N-terminal segment through the membrane. We compiled a large set of natural AMP sequences and MIC values to show that, statistically, the poly-R sequence motifs have, in average, a greater impact on the overall antimicrobial efficacy than equivalent sequences with poly-K motifs and similar charge densities. We discuss our observations in light of the unique structural and hydration properties of arginine residues.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 4","pages":"706–725"},"PeriodicalIF":4.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsbiomedchemau.5c00084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}