ACS Bio & Med Chem Au最新文献

{"title":"3-Hydroxy-Beta-Lactam Inhibitors of Dihydrofolate Synthetase","authors":"Brett Virgin-Downey,&nbsp;Luting Fang,&nbsp;Charles R. Nosal and Timothy A. Wencewicz*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c00036","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00036","url":null,"abstract":"<p >The 3-hydroxy-β-lactam (3-HβL) group derived from the natural product tabtoxinine-β-lactam (TβL), an inhibitor of glutamine synthetase, was repurposed to develop an inhibitor of dihydrofolate synthetase (DHFS). We show that replacement of the carboxyl group of <i>p</i>-amino-benzoic acid (PABA) with a 3-HβL moiety on the chemical scaffold of a folate mimic results in a potent inhibitor of DHFS. Using a combination of <i>in vitro</i> steady-state kinetics, enzyme-coupled assays, and molecular modeling, we validate the essential role of the 3-HβL group in DHFS inhibition. We provide an optimized synthesis of the 3-(<i>p</i>-aminophenyl)-3-HβL component via a sequence of the C–C bond-forming Henry reaction and a β-lactam ring-closing Grignard reaction. We demonstrate full elaboration to an antifolate scaffold via chemical or chemoenzymatic conjugation of the PABA analogue 3-(<i>p</i>-aminophenyl)-3-HβL to a pterin mimic. In this proof-of-concept study, we provide the first evidence that the 3-HβL group can be used as a general pharmacophore for inhibitors of enzymes in the ATP-dependent carboxylate-amine ligase superfamily through carboxylate replacement on substrate scaffolds, which could have broad therapeutic applications.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 4","pages":"637–649"},"PeriodicalIF":4.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsbiomedchemau.5c00036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863078","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":"Mitochondria-Targeting Biquaternary Ammonium Compounds: Pancreatic Anticancer Activity and Synergistic Interaction with Metformin","authors":"Maude Petit,&nbsp;Eugénie Daubas Prade and Andreea R. Schmitzer*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c00130","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00130","url":null,"abstract":"<p >Challenges in pancreatic cancer treatment primarily arise from chemotherapy resistance, cancer cell metastasis, and frequent late-stage diagnoses. These issues significantly compromise the effectiveness of standard treatments and highlight the urgent need for targeted approaches. In this context, we explored the anticancer potential of bis-quaternary ammonium-based compounds (BQACs), which remains largely uncharted. This study examines the structure–activity relationship of amphiphilic bicationic compounds as anticancer agents, focusing on their selectivity against pancreatic cancer cells. Our analysis revealed a potent antiproliferative effect associated with mitochondrial accumulation and subsequent mitochondrial membrane depolarization. Furthermore, combination therapies involving BQACs and chemotherapeutic drugs were explored to enhance treatment efficacy. Consequently, we propose a novel combination of BQACs with metformin, resulting in enhanced cellular uptake of the latter. The synergistic effect of the combination enables a significantly lower effective dose of metformin when used alongside BQACs to achieve therapeutic outcomes.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 4","pages":"553–564"},"PeriodicalIF":4.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsbiomedchemau.4c00130","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863074","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":"Graphene Oxide in Bone Regenerative Engineering: Current Challenges and Future Perspectives","authors":"Fatemeh S. Hosseini,&nbsp;Ho-Man Kan,&nbsp;Taraje Whitfield,&nbsp;Chrysoula Argyrou,&nbsp;Amir A. Abedini,&nbsp;Nicholas S. Allen and Cato T. Laurencin*,&nbsp;","doi":"10.1021/acsbiomedchemau.4c0015210.1021/acsbiomedchemau.4c00152","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.4c00152https://doi.org/10.1021/acsbiomedchemau.4c00152","url":null,"abstract":"<p >Owing to its exceptional physicochemical and biological properties, graphene oxide (GO), the oxidized form of graphene, has attracted considerable interest in bone regenerative engineering. The oxygen-functional groups on the backbone of GO enable biomolecule adherence, protein adsorption, cell adhesion, proliferation, differentiation, calcium ion adsorption and bone matrix mineralization. These oxygen functional groups enhance GO’s interaction with biological fluids, facilitating its hydrolytic biodegradation. Recent preclinical studies have indicated that GO effectively improves mechanical strength, immunomodulation, and osteoinduction when utilized within diverse matrix structures including natural and synthetic polymers and ceramics to induce osteogenesis. Advanced bone regenerative applications of GO, such as implant coating and delivery of bioactive compounds, have demonstrated enhanced osseointegration, antibacterial efficacy, and pro-healing microenvironments. However, there are still challenges regarding the high-quality large-scale synthesis and long-term biocompatibility of GO. Additionally, the variability in the characteristics of GO resulting from different synthesis methods demonstrates further challenges for therapeutic translation. This study provides a comprehensive review of the recent preclinical research on the translational potential of GO, discussing the convergence of its exceptional properties for use in bone regenerative engineering along with its current challenges and future perspectives.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"350–364 350–364"},"PeriodicalIF":3.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.4c00152","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144306031","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":"Graphene Oxide in Bone Regenerative Engineering: Current Challenges and Future Perspectives.","authors":"Fatemeh S Hosseini, Ho-Man Kan, Taraje Whitfield, Chrysoula Argyrou, Amir A Abedini, Nicholas S Allen, Cato T Laurencin","doi":"10.1021/acsbiomedchemau.4c00152","DOIUrl":"10.1021/acsbiomedchemau.4c00152","url":null,"abstract":"<p><p>Owing to its exceptional physicochemical and biological properties, graphene oxide (GO), the oxidized form of graphene, has attracted considerable interest in bone regenerative engineering. The oxygen-functional groups on the backbone of GO enable biomolecule adherence, protein adsorption, cell adhesion, proliferation, differentiation, calcium ion adsorption and bone matrix mineralization. These oxygen functional groups enhance GO's interaction with biological fluids, facilitating its hydrolytic biodegradation. Recent preclinical studies have indicated that GO effectively improves mechanical strength, immunomodulation, and osteoinduction when utilized within diverse matrix structures including natural and synthetic polymers and ceramics to induce osteogenesis. Advanced bone regenerative applications of GO, such as implant coating and delivery of bioactive compounds, have demonstrated enhanced osseointegration, antibacterial efficacy, and pro-healing microenvironments. However, there are still challenges regarding the high-quality large-scale synthesis and long-term biocompatibility of GO. Additionally, the variability in the characteristics of GO resulting from different synthesis methods demonstrates further challenges for therapeutic translation. This study provides a comprehensive review of the recent preclinical research on the translational potential of GO, discussing the convergence of its exceptional properties for use in bone regenerative engineering along with its current challenges and future perspectives.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"350-364"},"PeriodicalIF":3.8,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183520/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144486242","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":"Unlocking the Potential of Brazilian Plant Terpenes to Combat Antimicrobial Resistance","authors":"Danae K. R. Bardaji,&nbsp;Nagela B. S. Silva,&nbsp;Renata R. Miranda,&nbsp;Carlos Henrique G. Martins,&nbsp;Michael A. Savka and André O. Hudson*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c0006910.1021/acsbiomedchemau.5c00069","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00069https://doi.org/10.1021/acsbiomedchemau.5c00069","url":null,"abstract":"<p >The group of bacteria known as ESKAPE: <i>Enterococcus faecium</i>, <i>Staphylococcus aureus</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i>, and <i>Enterobacter</i> spp. are well recognized for their high virulence and pathogenicity, employing diverse modalities and mechanisms to resist multiple classes of clinically relevant antibiotics. Their capacity to evade treatment presents a major public health challenge, highlighting the urgent need for novel antibiotics to address the growing resistance crisis. The plant kingdom presents a promising avenue to this fight. Plants are naturally endowed with the genomic and proteomic machinery to synthesize a wide arsenal of secondary metabolites, including terpenes and terpenoids, which have demonstrated potent antimicrobial properties both as standalone agents and as synergists or enhancers of existing antibiotics. These plant-derived compounds often operate through mechanisms distinct from those of conventional antibiotics, offering a potentially effective solution against antibiotic-resistant bacteria. Brazil, home to some of the richest biodiversity on the planet, boasts 46,000 recorded plant species, with 250 new species identified annually. This review delves into the methods of preparing and isolating terpenes and terpenoids from plants, explores the techniques used to assess their antibacterial activity, and highlights ongoing research using Brazilian plants to target ESKAPE pathogens. This compilation of knowledge aims to establish a pipeline for evaluating the antibacterial potential of terpenes and terpenoids, contributing to efforts addressing the growing threat of antimicrobial resistance.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"365–378 365–378"},"PeriodicalIF":3.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.5c00069","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305881","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":"Unlocking the Potential of Brazilian Plant Terpenes to Combat Antimicrobial Resistance.","authors":"Danae K R Bardaji, Nagela B S Silva, Renata R Miranda, Carlos Henrique G Martins, Michael A Savka, André O Hudson","doi":"10.1021/acsbiomedchemau.5c00069","DOIUrl":"10.1021/acsbiomedchemau.5c00069","url":null,"abstract":"<p><p>The group of bacteria known as ESKAPE: <i>Enterococcus faecium</i>, <i>Staphylococcus aureus</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i>, and <i>Enterobacter</i> spp. are well recognized for their high virulence and pathogenicity, employing diverse modalities and mechanisms to resist multiple classes of clinically relevant antibiotics. Their capacity to evade treatment presents a major public health challenge, highlighting the urgent need for novel antibiotics to address the growing resistance crisis. The plant kingdom presents a promising avenue to this fight. Plants are naturally endowed with the genomic and proteomic machinery to synthesize a wide arsenal of secondary metabolites, including terpenes and terpenoids, which have demonstrated potent antimicrobial properties both as standalone agents and as synergists or enhancers of existing antibiotics. These plant-derived compounds often operate through mechanisms distinct from those of conventional antibiotics, offering a potentially effective solution against antibiotic-resistant bacteria. Brazil, home to some of the richest biodiversity on the planet, boasts 46,000 recorded plant species, with 250 new species identified annually. This review delves into the methods of preparing and isolating terpenes and terpenoids from plants, explores the techniques used to assess their antibacterial activity, and highlights ongoing research using Brazilian plants to target ESKAPE pathogens. This compilation of knowledge aims to establish a pipeline for evaluating the antibacterial potential of terpenes and terpenoids, contributing to efforts addressing the growing threat of antimicrobial resistance.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"365-378"},"PeriodicalIF":3.8,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183609/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144486249","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":"In Vitro and In Vivo Antifungal Efficacy and Safety of the CaDef2.1G27-K44 Peptide against the Neglected and Drug-Resistant Pathogen Candida krusei","authors":"Thomas Z. A. Guimarães,&nbsp;Érica O. Mello,&nbsp;Douglas R. Lucas,&nbsp;Filipe Z. Damica,&nbsp;Fadi S. S. Magalhães,&nbsp;Luís G. M. Basso,&nbsp;André O. Carvalho,&nbsp;Valdirene M. Gomes and Gabriel B. Taveira*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c00020","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00020","url":null,"abstract":"<p >The growing threat of fungal infections, driven by increasing drug resistance, has become a major global health concern. Candidiasis, a common human infection, is associated with high mortality, particularly in invasive cases. Among non-<i>albicans Candida</i> (NAC) species, <i>Candida krusei</i> (renamed <i>Pichia kudriavzevii</i>) is of clinical importance because of its intrinsic resistance to fluconazole, complicating treatment options. This study evaluated the antifungal efficacy and safety of the bioinspired peptide <i>Ca</i>Def2.1_G27-K44 (CDF-GK) against NAC species, with a specific focus on <i>C. krusei</i>, through a series of <i>in vitro</i> and <i>in vivo</i> tests. CDF-GK effectively inhibited the growth of several yeast species, including <i>C. glabrata</i>, <i>C. guilliermondii</i>, <i>C. bracarensis</i>, and <i>C. nivariensis</i>, with MIC values ranging from 3.12 to 200 μM. The peptide demonstrated particularly strong activity against <i>C. krusei</i>, with an MIC₁₀₀ of 25 μM, an MFC₁₀₀ of 50 μM, and an IC₅₀ of 5 μM, surpassing the effectiveness of fluconazole. Additionally, CDF-GK inhibited biofilm formation, caused 100% cell death within 1 h, permeabilized the cell membrane, interacted with ergosterol, induced oxidative stress, mitochondrial dysfunction, and vacuolar fragmentation, and entered the intracellular space of <i>C. krusei</i>. <i>In vivo</i> assays using <i>Galleria mellonella</i> larvae confirmed the low toxicity of CDF-GK, even at high concentrations, and significantly improved the survival of infected larvae with minimal activation of cellular and humoral immune responses. These findings indicate that CDF-GK holds great promise as a therapeutic agent for <i>C. krusei</i> infections, as it combines potent antifungal action with safety in both <i>in vitro</i> and <i>in vivo</i> models.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 4","pages":"620–636"},"PeriodicalIF":4.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acsbiomedchemau.5c00020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144863041","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":"Discovery of Iboga-Derived Ligands for the Sigma-2 Receptor","authors":"Alexander J. Hughes,&nbsp;Julie A. Talbert and Steven D. Townsend*,&nbsp;","doi":"10.1021/acsbiomedchemau.5c0001110.1021/acsbiomedchemau.5c00011","DOIUrl":"https://doi.org/10.1021/acsbiomedchemau.5c00011https://doi.org/10.1021/acsbiomedchemau.5c00011","url":null,"abstract":"<p >Substance use disorder (SUD) is a mental condition that affects a person’s brain and behavior, leading to a lack of control with alcohol, drug, and medication use. The lack of efficacious and novel treatments for SUD is a growing concern. As such, we have synthesized a series of iboga alkaloid derivatives and evaluated their receptor binding profiles against a panel of CNS-based proteins, which were performed at the National Institute of Mental Health Psychoactive Drug Screening Program. These studies revealed two compounds that exhibit high affinity for the sigma-2 receptor and introduce the iboga alkaloid framework as a new scaffold for the development of sigma-2 ligands.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"379–386 379–386"},"PeriodicalIF":3.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acsbiomedchemau.5c00011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144305720","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":"Discovery of Iboga-Derived Ligands for the Sigma‑2 Receptor.","authors":"Alexander J Hughes, Julie A Talbert, Steven D Townsend","doi":"10.1021/acsbiomedchemau.5c00011","DOIUrl":"10.1021/acsbiomedchemau.5c00011","url":null,"abstract":"<p><p>Substance use disorder (SUD) is a mental condition that affects a person's brain and behavior, leading to a lack of control with alcohol, drug, and medication use. The lack of efficacious and novel treatments for SUD is a growing concern. As such, we have synthesized a series of iboga alkaloid derivatives and evaluated their receptor binding profiles against a panel of CNS-based proteins, which were performed at the National Institute of Mental Health Psychoactive Drug Screening Program. These studies revealed two compounds that exhibit high affinity for the sigma-2 receptor and introduce the iboga alkaloid framework as a new scaffold for the development of sigma-2 ligands.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"379-386"},"PeriodicalIF":3.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12183592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144486240","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":"Leveraging the Capsular Polysaccharide Synthesis Pathway in <i>Streptococcus pneumoniae</i> as a Genetic Glycoengineering Platform.","authors":"Cheryl Kang-Rou Wong, Ye-Yu Chun, Tong Su, Lok-To Sham","doi":"10.1021/acsbiomedchemau.5c00010","DOIUrl":"10.1021/acsbiomedchemau.5c00010","url":null,"abstract":"<p><p>Engineering carbohydrates in living cells is one of the overarching goals of biology. In this Perspective, we discuss recent work in response to this challenge. Compared with eukaryotic cells, bacteria are fast-growing and genetically tractable. At the species level, glycans in prokaryotes are highly variable, contrasting with the homogeneity of surface glycans, such as capsular polysaccharides (CPSs), at the strain level. We exploited the conditional essentiality of the CPS synthesis pathway in <i>Streptococcus pneumoniae</i> to overcome the challenges of biochemically monitoring the engineered glycan products. While this strategy seems feasible, this glycoengineering platform is limited by the specificity of the capsule transporters and the glycosyltransferase inventories that can be introduced into the pneumococcus. Mutants that relax transporter specificity have been isolated, enabling us to inactivate otherwise essential glycosyltransferases. Ongoing work aims to harness this technology to synthesize medically relevant glycans, including Lewis antigens and tumor markers.</p>","PeriodicalId":29802,"journal":{"name":"ACS Bio & Med Chem Au","volume":"5 3","pages":"342-349"},"PeriodicalIF":3.8,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144486243","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}