Bioorganic & Medicinal Chemistry最新文献

{"title":"Truxillic acid monoamides as fatty acid binding protein 5 inhibitors","authors":"Chuanzhou Zhu ,&nbsp;Livia Schutz ,&nbsp;Kalani Jayanetti ,&nbsp;Kathryn Takemura ,&nbsp;Faniya Doswell ,&nbsp;Liqun Wang ,&nbsp;Iwao Ojima ,&nbsp;Martin Kaczocha","doi":"10.1016/j.bmc.2023.117464","DOIUrl":"10.1016/j.bmc.2023.117464","url":null,"abstract":"<div><p>Fatty acid binding proteins (FABPs) are intracellular chaperones that deliver bioactive lipids to cytosolic enzymes and nuclear receptors, thereby regulating diverse biological functions. FABP5 is a member of the FABP family that mediates endocannabinoid transport and inactivation, with pharmacological or genetic FABP5 inhibition conferring antinociceptive effects. Consequently, FABP5 inhibitors have emerged as promising analgesics and demonstrate antinociceptive activity in models of pain. Recently developed FABP5 inhibitors based upon the α-truxillic acid monoester (TAME) scaffold demonstrate high affinities for FABP5 but are commonly accompanied by reduced selectivity against related FABPs, notably FABP3 that is expressed in the heart, highlighting the need to identify additional scaffolds that afford enhanced selectivity while maintaining FABP5 potency. Here, we describe the synthesis and biological evaluation of truxillic acid monoamides (TAMADs) as potent, selective, and efficacious FABP5 inhibitors. Combining <em>in silico</em> molecular docking and <em>in vitro</em> binding assay approaches, our findings demonstrate that TAMADs exhibit exceptional selectivity against FABP3 and several compounds attain high FABP5 affinities. Examination of antinociceptive activity revealed that TAMADs and their corresponding TAMEs demonstrate comparable efficacy and temporal activity profiles <em>in vivo</em>. These results position TAMAD as a suitable scaffold for the development of FABP5 inhibitors with diminished FABP3 cross-reactivity.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"94 ","pages":"Article 117464"},"PeriodicalIF":3.5,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10608421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"“You’ve got the Body I’ve got the Brains” – Could the current AI-based tools replace the human ingenuity for designing new drug candidates?","authors":"Edeildo Ferreira da Silva-Júnior","doi":"10.1016/j.bmc.2023.117475","DOIUrl":"10.1016/j.bmc.2023.117475","url":null,"abstract":"<div><p><span>The emergence of artificial intelligence (AI) tools has transformed the landscape of drug<span><span> discovery, providing unprecedented speed, efficiency, and cost-effectiveness in the search for new therapeutics. From target identification to drug formulation and delivery, AI-driven algorithms have revolutionized various aspects of </span>medicinal chemistry, significantly accelerating the drug design process. Despite the transformative power of AI, this perspective article emphasizes the limitations of AI tools in drug discovery, requiring inventive skills of medicinal chemists. However, the article highlighted that there is a need for a harmonious integration of AI-based tools and human expertise in drug discovery. Such a synergistic approach promises to lead to groundbreaking therapies that address unmet medical needs and benefit humankind. As the world evolves technologically, the question remains: </span></span><em>When will AI tools effectively design and develop drugs?</em> The answer may lie in the seamless collaboration between AI and human researchers, unlocking transformative therapies that combat diseases effectively.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"94 ","pages":"Article 117475"},"PeriodicalIF":3.5,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41103056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the unexpected aggregation behavior of Pyrazole-Based compounds Targeting Mycobacterium tuberculosis UDP-Galactopyranose mutase","authors":"Dalia M. Ahmed ,&nbsp;David A.R. Sanders","doi":"10.1016/j.bmc.2023.117466","DOIUrl":"10.1016/j.bmc.2023.117466","url":null,"abstract":"<div><p>A pyrazole-based compound, <strong>MS208</strong><span>, was previously identified as an inhibitor of UDP-Galactopyranose Mutase from </span><span><em>Mycobacterium tuberculosis</em></span> (<em>Mt</em><span>UGM). Targeting this enzyme<span> is a novel therapeutic strategy for the development of new antituberculosis agents because </span></span><em>Mt</em><span>UGM is an essential enzyme for the bacterial cell wall synthesis and it is not present in human. It was proposed that </span><strong>MS208</strong><span> targets an allosteric site in </span><em>Mt</em>UGM as <strong>MS208</strong> followed a mixed inhibition model. <strong>DA10</strong>, an <strong>MS208</strong><span> analogue, showed competitive inhibition rather than mixed inhibition. In this paper, we have used an integrated biophysical approach, including thermal shift assays, dynamic light scattering and nuclear magnetic resonance experiments, to show that </span><strong>MS208</strong> and many analogues displayed unexpected aggregation behavior against <em>Mt</em>UGM.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"94 ","pages":"Article 117466"},"PeriodicalIF":3.5,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10308952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structure-activity relationship studies and biological properties evaluation of peptidic NRP-1 ligands: Investigation of N-terminal cysteine importance","authors":"Anna K. Puszko ,&nbsp;Piotr Sosnowski ,&nbsp;Olivier Hermine ,&nbsp;Gérard Hopfgartner ,&nbsp;Yves Lepelletier ,&nbsp;Aleksandra Misicka","doi":"10.1016/j.bmc.2023.117482","DOIUrl":"10.1016/j.bmc.2023.117482","url":null,"abstract":"<div><p>Neuropilin-1 (NRP-1) is a major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2). It may also stimulate tumour growth and metastasis independently of VEGF-A₁₆₅. These functions make VEGF-A₁₆₅/NRP-1 complex formation and its inhibition of great interest, where NRP-1 is the target for which effective ligands are sought. Design of peptide-like inhibitors represent a strategy with great potential in the treatment of NRP-1-related disorders. Here, we present the synthesis, molecular modelling, structure-activity relationship studies as well as biological evaluation of peptides with the branched sequences H₂N-X-Lys(<em>h</em>Arg)-Dab-Oic-Arg-OH and H<em>₂</em>N-Lys(X-<em>h</em>Arg)-Dab-Oic-Arg-OH. Two of the designed peptides, in which Cys was inserted in X position, expressed high affinity (∼40 nM value) for NRP-1 and were resistant to enzymatic digestion in human serum. Moreover, peptide/NRP-1 complex promoted fast intracytoplasmic protein trafficking towards the plasma membrane in breast cancer cells. Our results suggest that these compounds might be good candidates for further development of VEGF-A₁₆₅/NRP-1 inhibitors.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"94 ","pages":"Article 117482"},"PeriodicalIF":3.5,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089623003309/pdfft?md5=3cd1c97dc2ceefc37b22b0bab927ca12&pid=1-s2.0-S0968089623003309-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41092408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay","authors":"Meiling Shen ,&nbsp;Lingfeng Li ,&nbsp;Yue Li ,&nbsp;Xi Gu ,&nbsp;Longhui Bai ,&nbsp;Chengfeng Xia ,&nbsp;Wenyong Xiong ,&nbsp;Zhili Zuo","doi":"10.1016/j.bmc.2023.117477","DOIUrl":"10.1016/j.bmc.2023.117477","url":null,"abstract":"<div><p>The transient receptor potential canonical channel 5 (TRPC5), a member of the TRPC family, plays a crucial role in the regulation of various physiological activities and diseases, including those related to the central nervous system, cardiovascular system, kidney, and cancer. As a nonselective cation channel, TRPC5 mainly controls the influx of extracellular Ca²⁺ into cells, thereby modulating cellular depolarization and intracellular ion concentration. Inhibition of TRPC5 by small molecules presents a promising approach for the treatment of TRPC5-associated diseases. In this study, we conducted a comprehensive virtual screening of more than 1.5 million molecules from the Chemdiv database (<span>https://www.chemdiv.com</span><svg><path></path></svg>) to identify potential inhibitors of hTRPC5, utilizing the published structures and binding sites of hTRPC5 as a basis. Lipinski's rule, Veber's rule, PAINS filters, pharmacophore analysis, molecular docking, ADMET evaluation and cluster analysis methods were applied for the screening. From this rigorous screening process, 18 candidates exhibiting higher affinities to hTRPC5 were subsequently evaluated for their inhibitory effects on Ca²⁺ influx using a fluorescence-based assay. Notably, two molecules, namely SML-1 and SML-13, demonstrated significant inhibition of intracellular Ca²⁺ levels in hTRPC5-overexpressing HEK 293T cells, with IC₅₀ values of 10.2 μM and 10.3 μM, respectively. These findings highlight SML-1 and SML-13 as potential lead molecules for the development of therapeutics targeting hTRPC5 and its associated physiological activities and diseases.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"94 ","pages":"Article 117477"},"PeriodicalIF":3.5,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design of a structure-activity relationship model of vitamin K epoxide reductase (VKORC1) inhibitors combining chemical synthesis of new compounds, enzymatic assays and molecular modelling","authors":"Nolan Chatron ,&nbsp;Manon Boulven ,&nbsp;Adrien Montagut-Romans ,&nbsp;Flavien Ponsot ,&nbsp;Maïwenn Jacolot ,&nbsp;Hervé Caruel ,&nbsp;Etienne Benoît ,&nbsp;Florence Popowycz ,&nbsp;Virginie Lattard","doi":"10.1016/j.bmc.2023.117453","DOIUrl":"10.1016/j.bmc.2023.117453","url":null,"abstract":"<div><p><span><span>Vitamin K antagonists (VKAs) </span>anticoagulants have been used since the 1950s as medicines and </span>rodenticides<span><span>. These molecules are mainly 4-hydroxycoumarin derivatives and act by inhibiting the vitamin K epoxide<span> reductase (VKORC1), an endoplasmic reticulum membrane<span> resident enzyme. However, many VKORC1 mutations have been reported over the last decade, inducing VKAs resistances and thus </span></span></span>treatments<span><span><span> failures. Although studies have reported experimental and computational investigations of VKAs based on VKORC1 structural homology<span> models, the development of new effective anticoagulants has been quite complex due to the lack of structural data and reliable structure–activity relationships. However, the recent publication of VKORC1 crystal structure provides new information for further studies. Based on these findings, we combined chemical synthesis, enzymatic assays and molecular modelling methods to design a structure–activity relationship (SAR) model. Our results proved that the </span></span>lipophilicity<span>, the membrane permeability of inhibitors and their affinity towards human VKORC1 enzyme are the main characteristics for potent anticoagulants. Our SAR model managed to rank compounds according to their ability to inhibit the human VKORC1. Such a tool might constitute an alternative to evaluate new molecules potency before their chemical synthesis and </span></span>biological assessment and might assist the development of new VKAs.</span></span></p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"94 ","pages":"Article 117453"},"PeriodicalIF":3.5,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41098971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selenoneine-inspired selenohydantoins with glutathione peroxidase-like activity","authors":"Rama Alhasan ,&nbsp;Guilherme M. Martins ,&nbsp;Pedro P. de Castro ,&nbsp;Rahman Shah Zaib Saleem ,&nbsp;Ali Zaiter ,&nbsp;Isabelle Fries-Raeth ,&nbsp;Alexandra Kleinclauss ,&nbsp;Caroline Perrin-Sarrado ,&nbsp;Patrick Chaimbault ,&nbsp;Eufrânio N. da Silva Júnior ,&nbsp;Caroline Gaucher ,&nbsp;Claus Jacob","doi":"10.1016/j.bmc.2023.117479","DOIUrl":"10.1016/j.bmc.2023.117479","url":null,"abstract":"<div><p><span><span>Chronic diseases such as cystic fibrosis<span>, inflammatory bowel diseases, </span></span>rheumatoid arthritis<span>, and cardiovascular illness have been linked to a decrease in selenium levels and an increase in oxidative stress<span><span>. Selenium is an essential trace element that exhibits antioxidant<span><span> properties, with selenocysteine<span><span> enzymes like </span>glutathione peroxidase being particularly effective at reducing peroxides. In this study, a series of synthetic </span></span>organoselenium compounds<span> were synthesized and evaluated for their potential antioxidant activities<span>. The new selenohydantoin molecules were inspired by selenoneine and synthesized using straightforward methods. Their antioxidant potential was evaluated and proven using classical radical scavenging and metal-reducing methods. The selenohydantoin derivatives exhibited glutathione peroxidase-like activity, reducing hydroperoxides<span>. Theoretical calculations using Density Functional Theory (DFT) revealed the selenone isomer to be the only one occurring in solution, with selenolate as a possible tautomeric form in the presence of a basic species. Cytocompatibility assays indicated that the selenohydantoin derivatives were non-toxic to primary human </span></span></span></span></span>aortic smooth muscle cells, paving the way for further biological evaluations of their antioxidant activity. The results suggest that selenohydantoin derivatives with trifluoro-methyl (-CF</span></span></span>₃) and chlorine (-Cl) substituents have significant activities and could be potential candidates for further biological trials. These compounds may contribute to the development of effective therapies for chronic diseases such cardiovascular diseases.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"94 ","pages":"Article 117479"},"PeriodicalIF":3.5,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41090681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Designing peptide amphiphiles as novel antibacterials and antibiotic adjuvants against gram-negative bacteria","authors":"Huihua Xing ,&nbsp;Vanessa Loya-Perez ,&nbsp;Joshua Franzen ,&nbsp;Paul W. Denton ,&nbsp;Martin Conda-Sheridan ,&nbsp;Nathalia Rodrigues de Almeida","doi":"10.1016/j.bmc.2023.117481","DOIUrl":"10.1016/j.bmc.2023.117481","url":null,"abstract":"<div><p>Gram-negative strains are intrinsically resistant to most antibiotics due to the robust and impermeable characteristic of their outer membrane. Self-assembling cationic peptide amphiphiles (PAs) have the ability to disrupt bacteria membranes, constituting an excellent antibacterial alternative to small molecule drugs that can be used alone or as antibiotic adjuvants to overcome bacteria resistance. PA1 (C₁₆KHKHK), self-assembled into micelles, which exhibited low antibacterial activity against all strains tested, and showed strong synergistic antibacterial activity in combination with Vancomycin with a Fractional Inhibitory Concentration index (FIC<em>i</em>) of 0.15 against <em>E. coli.</em> The molecules, PA2 (C₁₆KRKR) and PA3 (C₁₆<span>AAAKRKR), also self-assembled into micelles, displayed a broad-spectrum antibacterial activity against all strains tested, and low susceptibility to resistance development over 21 days. Finally, PA1, PA 2 and PA3 displayed low cytotoxicity against mammalian cells, and PA2 showed a potent antibacterial activity and low toxicity in preliminary </span><em>in vivo</em> models using <em>G. mellonella</em>. The results show that PAs are a great platform for the future development of effective antibiotics to slow down the antibiotic resistance and can act as antibiotic adjuvants with synergistic mechanism of action, which can be repurposed for use with existing antibiotics commonly used to treat gram-positive bacteria to treat infections caused by gram-negative bacteria.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"94 ","pages":"Article 117481"},"PeriodicalIF":3.5,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41093439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Selective modifications of lactose and N-acetyllactosamine with sulfate and aromatic bulky groups unveil unique structural insights in galectin-1-ligand recognition","authors":"Mora Massaro ,&nbsp;Alejandro J. Cagnoni ,&nbsp;Francisco J. Medrano ,&nbsp;Juan M. Pérez-Sáez ,&nbsp;Shuay Abdullayev ,&nbsp;Karima Belkhadem ,&nbsp;Karina V. Mariño ,&nbsp;Antonio Romero ,&nbsp;René Roy ,&nbsp;Gabriel A. Rabinovich","doi":"10.1016/j.bmc.2023.117480","DOIUrl":"10.1016/j.bmc.2023.117480","url":null,"abstract":"<div><p><span><span>Galectins, a family of endogenous glycan-binding proteins, play crucial roles in a broad range of physiological and pathological processes. Galectin-1 (Gal-1), a proto-type member of this family, is overexpressed in several cancers and plays critical roles in tumor-immune escape, </span>angiogenesis<span> and metastasis. Thus, generation of high-affinity Gal-1 inhibitors emerges as an attractive therapeutic approach for a wide range of neoplastic conditions. Small-molecule carbohydrate inhibitors based on lactose (Lac) and </span></span><em>N</em><span><span>-acetyllactosamine (LacNAc) structures have been tested showing different results. In this study, we evaluated Lac- and LacNAc-based compounds with specific chemical modifications at key positions as Gal-1 ligands by competitive solid-phase assays (SPA) and isothermal titration calorimetry<span> (ITC). Both assays showed excellent correlation, highlighting that lactosides bearing bulky aromatic groups at the anomeric carbon and sulfate groups at the O3′ position exhibited the highest binding affinities. To dissect the atomistic determinants for preferential affinity of the different tested Gal-1 ligands, </span></span>molecular docking simulations<span> were conducted and PRODIGY-LIG structure-based method was employed to predict binding affinity in protein–ligand complexes. Notably, calculated binding free energies derived from the molecular docking were in accordance with experimental values determined by SPA and ITC, showing excellent correlation between theoretical and experimental approaches. Moreover, this analysis showed that 3′-O-sulfate groups interact with residues of the Gal-1 subsite B, mainly with Asn33, while the ester groups of the aromatic anomeric group interact with Gly69 and Thr70 at Gal-1 subsite E, extending deeper into the pocket, which could account for the enhanced binding affinity. This study contributes to the rational design of highly optimized Gal-1 inhibitors to be further studied in cancer models and other pathologic conditions.</span></span></p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"94 ","pages":"Article 117480"},"PeriodicalIF":3.5,"publicationDate":"2023-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41091586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reading and erasing of histone crotonyllysine mimics by the AF9 YEATS domain and SIRT2 deacylase","authors":"Nurgül Bilgin,&nbsp;Vildan A. Türkmen,&nbsp;Nesrin Hammami,&nbsp;Nadja R. Christensen,&nbsp;Jordi C.J. Hintzen,&nbsp;Jasmin Mecinović","doi":"10.1016/j.bmc.2023.117500","DOIUrl":"10.1016/j.bmc.2023.117500","url":null,"abstract":"<div><p>Lysine acylations on histones and their recognition by chromatin-binding reader domains and removal by histone deacylases function as an important mechanism for eukaryotic gene regulation. Histone lysine crotonylation (Kcr) is an epigenetic mark associated with active transcription, and its installation and removal are dynamically regulated by cellular epigenetic enzymes. Here, we report binding studies and enzyme assays with histone H3K9 peptides bearing simplest Kcr analogs with varying hydrocarbon chain length, bulkiness, rigidity and polarity. We demonstrate that the AF9 YEATS domain displays selectivity for binding of different acylation modifications on histone H3K9 peptides and exhibits preference for bulkier cinnamoylated lysine over crotonylated lysine and its mimics. SIRT2 shows deacylase activity against most of acylated H3K9 peptides bearing different crotonyllysine mimics, however, it displays a poor ability for the removal of cinnamoyl and trifluorocrotonyl groups. These results demonstrate different substrate selectivities of epigenetic proteins acting on crotonyllysine and pave the way for rational design and development of AF9 YEATS and SIRT2 inhibitors for treatment of human diseases, including cancer.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"95 ","pages":"Article 117500"},"PeriodicalIF":3.5,"publicationDate":"2023-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0968089623003486/pdfft?md5=912d9bc984b648de18cc63d7c2902cb4&pid=1-s2.0-S0968089623003486-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41231045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}