Bioconjugate Chemistry Bioconjugate最新文献

{"title":"Computational Approaches for Antimicrobial Peptide Delivery.","authors":"Thuanny Borba Rios, Samilla Beatriz Rezende, Mariana Rocha Maximiano, Marlon Henrique Cardoso, Martin Malmsten, Cesar de la Fuente-Nunez, Octávio Luiz Franco","doi":"10.1021/acs.bioconjchem.4c00406","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00406","url":null,"abstract":"<p><p>Peptides constitute alternative molecules for the treatment of infections caused by bacteria, viruses, fungi, and protozoa. However, their therapeutic effectiveness is often limited by enzymatic degradation, chemical and physical instability, and toxicity toward healthy human cells. To improve their pharmacokinetic (PK) and pharmacodynamic (PD) profiles, novel routes of administration are being explored. Among these, nanoparticles have shown promise as potential carriers for peptides, although the design of delivery vehicles remains a slow and painstaking process, heavily reliant on trial and error. Recently, computational approaches have been introduced to accelerate the development of effective drug delivery systems for peptides. Here we present an overview of some of these computational strategies and discuss their potential to optimize drug development and delivery.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic Positron Emission Tomography Imaging of an Optimized CD38-Targeted ⁶⁸Ga-Labeled Peptide in Multiple Myeloma: A Pilot Study.","authors":"Qi Yang, Lele Song, Zhao Chen, Yongkang Qiu, Tianyao Wang, Xinyao Sun, Wenpeng Huang, Cuicui Li, Zihua Wang, Lei Kang","doi":"10.1021/acs.bioconjchem.4c00497","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00497","url":null,"abstract":"<p><p>Multiple myeloma (MM) is an incurable disease characterized by its clinical and prognostic heterogeneity. Despite conventional chemotherapy and autologous hematopoietic stem cell transplantation, the management of relapsed and refractory MM disease poses significant challenges, both medically and socioeconomically. CD38, highly expressed on the surface of MM cells, serves as a distinct tumor biological target in MM. Peptides offer advantages over antibodies, enabling precise tumor imaging and facilitating early tumor diagnosis and dynamic immunotherapy monitoring. In this study, we developed PF381, a CD38-targeted peptide, and investigated its role in diagnosis, biodistribution, and dosimetry through ⁶⁸Ga-labeling for preclinical evaluation in tumor-bearing models. We screened a microchip-based combinatorial chemistry peptide library to obtain the amino acid sequence of PF381. Affinity for human CD38 was evaluated by SPRi. PF381 was conjugated with DOTA for radiolabeling with ⁶⁸Ga, and the complex was characterized by HPLC. PET imaging was performed in murine tumor models after the administration of [⁶⁸Ga]Ga-DOTA-PF381. Biodistribution analysis compared CD38-positive H929 and CD38-negative U266 tumors, and human radiation dosimetry was estimated. Tumor sections were stained for CD38 expression. SPRi showed that PF381 had a high affinity for CD38 with a KD of 2.49 × 10^-8 M. HPLC measured a radiolabeling efficiency of 78.45 ± 7.91% for [⁶⁸Ga]Ga-DOTA-PF381, with >98% radiochemical purity. PET imaging revealed rapid and persistent accumulation of radioactivity in CD38-positive H929 tumors, contrasting with negligible uptake in CD38-negative U266 tumors. Biodistribution confirmed higher uptake in H929 tumors (0.75 ± 0.03%ID/g) vs U266 (0.26 ± 0.08%ID/g, <i>P</i> < 0.001). The kidney received the highest radiation dose (3.57 × 10^-02 mSv/MBq), with an effective dose of 1.41 × 10^-02 mSv/MBq. Immunofluorescence imaging supported PET and biodistribution findings. We developed a novel peptide targeting CD38 and proved that ⁶⁸Ga-labeled PF381 had rapid targeting and good tumor penetration capabilities. Therefore, ⁶⁸Ga-labeled PF381 could achieve high sensitivity in vivo imaging for CD38-positive hematological malignancies.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612606","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Online searches shape climate views","authors":"David M. Markowitz","doi":"10.1038/s41558-024-02118-8","DOIUrl":"https://doi.org/10.1038/s41558-024-02118-8","url":null,"abstract":"Online image search results depict climate change differently across the world. Countries with high (versus low) levels of climate concern encounter more emotional images, creating a difference that can change how people think and feel about climate change.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"14 1","pages":""},"PeriodicalIF":30.7,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Publisher Correction: Recent advances in the diagnosis and management of neuropsychiatric lupus","authors":"Alexandra C. Legge, John G. Hanly","doi":"10.1038/s41584-024-01193-7","DOIUrl":"https://doi.org/10.1038/s41584-024-01193-7","url":null,"abstract":"<p>Correction to: <i>Nature Reviews Rheumatology</i> https://doi.org/10.1038/s41584-024-01163-z, published online 2 October 2024.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"62 1","pages":""},"PeriodicalIF":33.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quizartinib: a potent and selective FLT3 inhibitor for the treatment of patients with FLT3-ITD–positive AML","authors":"Jorge Cortes","doi":"10.1186/s13045-024-01617-7","DOIUrl":"https://doi.org/10.1186/s13045-024-01617-7","url":null,"abstract":"Mutations in FMS-related receptor tyrosine kinase 3 (FLT3) are among the most common alterations in acute myeloid leukemia (AML), present in ≈30% of newly diagnosed AML cases. Internal tandem duplications (ITD) in FLT3 (FLT3-ITD) occur in ≈25% of newly diagnosed AML cases and are associated with unfavorable outcomes. Quizartinib (formerly AC220) is a novel, second-generation, highly potent, and selective type II FLT3 inhibitor. Quizartinib is approved in Japan as monotherapy for the treatment of adult patients with FLT3-ITD–positive relapsed/refractory (R/R) AML. Quizartinib is also approved in the United States, Japan, Europe, and United Kingdom in combination with chemotherapy during induction and consolidation, and as maintenance monotherapy (but, in the United States, not after allogeneic hematopoietic cell transplantation [allo-HCT]), for the treatment of adult patients with newly diagnosed FLT3-ITD–positive AML. In this review, we summarize preclinical studies that established quizartinib as a potent and selective type II FLT3 inhibitor as well as early and pivotal phase 3 clinical studies (QuANTUM-R and QuANTUM-First) that led to the approvals of quizartinib. We also summarize mechanisms of resistance to quizartinib along with its safety profile. Furthermore, we review the ongoing post hoc analyses of the QuANTUM-First data elucidating the impact of allo-HCT, the presence of measurable residual disease, and number and length of ITD on the clinical outcomes of quizartinib. We also describe the impact of quizartinib on patient-reported outcomes. Finally, we highlight some of the ongoing studies that test quizartinib in patients with FLT3-ITD–positive AML, patients with FLT3-ITD–negative AML, in both the first-line and R/R settings, in patients fit or unfit for intensive chemotherapy, including studies for quizartinib-based combination with other compounds such as decitabine and venetoclax. Future research should aim to further optimize the clinical value of quizartinib and explore its use in additional clinical settings, which could be achieved by testing quizartinib with other drugs, better characterization of the mechanisms of resistance, identification of the role of quizartinib as a maintenance therapy after allo-HCT, and investigating quizartinib in patients with FLT3-ITD–negative AML.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"51 3 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fine-Tuned \"Click\" Functionalization of PAMAM Dendrimers with a Linear Fluorinated Guanidino Linker: Synthesis, Characterization, and Applications.","authors":"Carola Romani, Paola Gagni, Maria Enrica Di Pietro, Monica Sani, Mattia Sponchioni, Alessandro Volonterio","doi":"10.1021/acs.bioconjchem.4c00434","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00434","url":null,"abstract":"<p><p>This study presents the synthesis, characterization, and application of multifunctional PAMAM G2 and G4 dendrimers decorated with a linear fluorinated guanidino linker designed to improve gene delivery efficiency while minimizing cytotoxicity. For the first time, we were able to fine-tune the degree of grafting (DG) during the functionalization process through efficient \"click\" Michael addition, achieving the synthesis of a collection of six PAMAM conjugates that showed a significant enhancement in transfection efficiency (TE), surpassing the performance of traditional nonviral vectors. The incorporation of fluorinated moieties not only facilitated better deoxyribonucleic acid (DNA) condensation and TE but also introduced potential applications in ¹⁹F magnetic resonance imaging thanks to the sharp and intense fluorine nuclear magnetic resonance signals and favorable relaxation parameters. The new dendrimer conjugates demonstrated a promising balance between low cytotoxicity and high TE, with the low-generation PAMAM G2 with lower DG being the best-performing conjugate, making them strong candidates for further development in gene therapy. These findings highlight the potential of these multifunctional PAMAM dendrimers as efficient, nontoxic, and trackable gene delivery vectors.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Internet image search outputs propagate climate change sentiment and impact policy support","authors":"Michael Berkebile-Weinberg, Runji Gao, Rachel Tang, Madalina Vlasceanu","doi":"10.1038/s41558-024-02178-w","DOIUrl":"https://doi.org/10.1038/s41558-024-02178-w","url":null,"abstract":"<p>A critical step in tackling climate change involves structural, system-level changes facilitating action. Despite their ubiquity, little is known about how internet search algorithms portray climate change, and how these portrayals impact concern and action. In a sample of 49 countries, we found that nationwide climate concern, but not nation-level climate impact, predicted the emotional arousal caused by climate change Google Image Search outputs, as rated by a naive sample (<i>n</i> = 383). In a follow-up experiment we randomly assigned another sample (<i>n</i> = 899) to receive the climate change image outputs resulting from searches conducted in countries high or low in pre-existing climate concern, and found that participants exposed to images from countries with high pre-existing concern (compared to low) became more concerned about climate change, supportive of climate policy and likely to act pro-environmentally, suggesting a cycle of climate sentiment propagation systemically facilitated by internet search algorithms. We discuss the implications of these findings for climate action interventions.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"95 1","pages":""},"PeriodicalIF":30.7,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo gene editing and in situ generation of chimeric antigen receptor cells for next-generation cancer immunotherapy","authors":"Weiyue Zhang, Xin Huang","doi":"10.1186/s13045-024-01633-7","DOIUrl":"https://doi.org/10.1186/s13045-024-01633-7","url":null,"abstract":"Chimeric antigen receptor (CAR) cell therapy has achieved groundbreaking success in treating hematological malignancies. However, its application to solid tumors remains challenging due to complex manufacturing processes, limited in vivo persistence, and transient therapeutic effects. In vivo CAR-immune cells induced by gene delivery systems loaded with CAR genes and gene-editing tools have shown efficiency for anti-tumor immunotherapy. In situ programming of autologous immune cells avoids the safety concerns of allogeneic immune cells, and the manufacture of gene delivery systems could be standardized. Therefore, the in vivo editing and in situ generation of CAR-immune cells might potentially overcome the abovementioned limitations of current CAR cell therapy. This review mainly focuses on CAR structures, gene-editing tools, and gene delivery techniques applied in anti-tumor immunotherapy to help design and develop in situ CAR-immune cell therapy. The recent applications of in vivo CAR-immune cell therapy in both hematologic malignancies and solid tumors are investigated. To sum up, the in vivo editing and in situ generation of CAR therapy holds promise for offering a practical, cost-effective, efficient, safe, and widely applicable approach to the next-generation anti-tumor immunotherapy.","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":"63 1","pages":""},"PeriodicalIF":28.5,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142601200","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improved Large-Scale Synthesis of Acridonylalanine for Diverse Peptide and Protein Applications.","authors":"Jason G Marmorstein, Vinayak V Pagar, Eshe Hummingbird, Ibrahim G Saleh, Hoang Anh T Phan, Yanan Chang, Kyle D Shaffer, Yarra Venkatesh, Ivan J Dmochowski, Kathleen J Stebe, E James Petersson","doi":"10.1021/acs.bioconjchem.4c00411","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00411","url":null,"abstract":"<p><p>Fluorescent unnatural amino acids give biochemists, biophysicists, and bioengineers new ways to probe the properties of proteins and peptides. Here, the synthesis of acridon-2-ylalanine (Acd) is optimized for large-scale production to enable ribosomal incorporation through genetic code expansion (GCE), and fluorenylmethoxycarbonyl (Fmoc)-protected Acd is prepared for solid-phase peptide synthesis (SPPS). We demonstrate the utility of Acd in several applications: first, Acd quenching by Tyr is used in the design of fluorescent protease sensors made by SPPS. Second, we demonstrate Acd incorporation into a lanthanide-binding peptide that is generated either by GCE or by SPPS and demonstrate the utility of Acd for sensitizing the emission of Eu³⁺. Finally, Acd is inserted into the intrinsically disordered protein, α-synuclein, using GCE and used to study ion binding and aggregation.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual Responsive Emulsions Based on Amphiphilic Elastin-like Polypeptide Bioconjugates.","authors":"Laurianne Simon, Dongxu Zhou, Anita Coeurvolan, Vincent Lapinte, Sébastien Lecommandoux, Elisabeth Garanger, Sylvie Bégu","doi":"10.1021/acs.bioconjchem.4c00412","DOIUrl":"https://doi.org/10.1021/acs.bioconjchem.4c00412","url":null,"abstract":"<p><p>To achieve the desired therapeutic response, drug delivery systems must ensure the controlled release of the loaded content at the targeted site. One possible strategy relies on the improvement of conventional drug delivery systems. To do so, smart polymers, able to change their behavior upon chemical, physical, or biological stimuli, can be used. In this context, this study aims to evaluate the potential of natural amphiphilic smart elastin-like polypeptides grafted with alkyl chains (ELP-<i>g</i>-Bu) to stabilize conventional oil-in-water emulsions and trigger the release of loaded molecules upon dual stimuli. With butyl pendant chains and methionine residues, the macromolecular surfactant ELP-<i>g</i>-Bu demonstrated a modification of physicochemical properties, looking at critical aggregation concentration, upon both temperature and oxidation stimuli. The macromolecular surfactant was then able to stabilize a paraffin-oil-in-water emulsion. The ELP-<i>g</i>-Bu emulsion presented a droplet size of 9 ± 1 μm and stability for at least a month at 4 and 25 °C. After successful loading of a fluorescent lipophilic molecule used as a drug model, a complete destabilization of the ELP-<i>g</i>-Bu emulsion and burst release of the content was achieved with thermal triggering at 42 °C. In oxidative conditions, a partial release was measured, which can be improved by increasing the number of oxidable thioether groups. Overall, these dually responsive amphiphilic ELP-<i>g</i>-Bu demonstrated their potential for smart-polymer-based drug delivery systems that can be promising for inflammatory disease treatment as increased temperature and radical oxygen species are present in such cases.</p>","PeriodicalId":29,"journal":{"name":"Bioconjugate Chemistry Bioconjugate","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}