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Ground-breaking research in disease biology and continuous efforts in method development have uncovered a range of potential new drug targets. Increasingly, the drug discovery process is informed by technologies involving chemical probes as tools. Applications for chemical probes comprise target identification and assessment, as well as the qualification of small molecules as chemical starting points and drug candidates. Progress in probe chemistry has opened the way to novel assay formats and pharmaceutical compound classes. The European Federation of Medicinal Chemistry and Chemical Biology (EFMC) has launched the Chemical Biology Initiative to advance science in the field of medicinal chemistry and chemical biology, while representing all members of this extended scientific community. This review provides an overview of the many important developments in the field of chemical biology that have happened at the lively interface of academic and industrial research.
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Química Farmacêutica , Descoberta de Drogas , Sistemas de Liberação de Medicamentos , BiologiaRESUMO
Targeting RNA with small molecules is a major challenge of current medicinal chemistry, and the identification and design of original scaffolds able to selectively interact with an RNA target remains difficult. Various approaches have been developed based on classical medicinal chemistry strategies (fragment-based drug design, dynamic combinatorial chemistry, HTS or DNA-encoded libraries) as well as on advanced structural biology and biochemistry methodologies (such as X-ray, cryo-EM, NMR, or SHAPE). Here, we report the de novo design, synthesis, and biological evaluation of RNA ligands by using a straightforward and sustainable chemistry combined with molecular docking and biochemical and biophysical studies that allowed us to identify a novel pharmacophore for RNA binding. Specifically, we focused on targeting the biogenesis of microRNA-21, the well-known oncogene. This led us not only to promising inhibitors but also to a better understanding of the interactions between the small-molecule compounds and the RNA target paving the way for the rational design of efficient inhibitors with potential anticancer activity.
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Desenho de Fármacos , MicroRNAs , Simulação de Acoplamento Molecular , Técnicas de Química Combinatória , LigantesRESUMO
The European Federation for Medicinal chemistry and Chemical biology (EFMC) is a federation of learned societies. It groups organizations of European scientists working in a dynamic field spanning chemical biology and medicinal chemistry. New ideas, tools, and technologies emerging from a wide array of scientific disciplines continuously energize this rapidly evolving area. Medicinal chemistry is the design, synthesis, and optimization of biologically active molecules aimed at discovering new drug candidates - a mission that in many ways overlaps with the scope of chemical biology. Chemical biology is by now a mature field of science for which a more precise definition of what it encompasses, in the frame of EFMC, is timely. This article discusses chemical biology as currently understood by EFMC, including all activities dealing with the design and synthesis of biologically active chemical tools and their use to probe, characterize, or influence biological systems.
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Preparações Farmacêuticas/química , Química Farmacêutica , Europa (Continente) , Humanos , Preparações Farmacêuticas/síntese químicaRESUMO
Natural aminoglycosides are therapeutically useful antibiotics and very efficient RNA ligands. They are oligosaccharides that contain several ammonium groups able to interfere with the translation process in prokaryotes upon binding to bacterial ribosomal RNA (rRNA), and thus, impairing protein synthesis. Even if aminoglycosides are commonly used in therapy, these RNA binders lack selectivity and are able to bind to a wide number of RNA sequences/structures. This is one of the reasons for their toxicity and limited applications in therapy. At the same time, the ability of aminoglycosides to bind to various RNAs renders them a great source of inspiration for the synthesis of new binders with improved affinity and specificity toward several therapeutically relevant RNA targets. Thus, a number of studies have been performed on these complex and highly functionalized compounds, leading to the development of various synthetic methodologies toward the synthesis of conjugated aminoglycosides. The aim of this review is to highlight recent progress in the field of aminoglycoside conjugation, paying particular attention to modifications performed toward the improvement of affinity and especially to the selectivity of the resulting compounds. This will help readers to understand how to introduce a desired chemical modification for future developments of RNA ligands as antibiotics, antiviral, and anticancer compounds.
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Aminoglicosídeos , RNA , Antibacterianos/farmacologia , Ligantes , RNA Bacteriano/químicaRESUMO
MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human cancers, thus being oncogenic. The inhibition of oncogenic miRNAs (defined as the blocking of miRNAs' production or function) would find application in the therapy of different types of cancer in which these miRNAs are implicated. In this work, we describe the design and synthesis of new small-molecule RNA ligands with the aim of inhibiting Dicer-mediated processing of oncogenic miRNAs. One of the synthesized compound (4b) composed of the aminoglycoside neomycin conjugated to an artificial nucleobase and to amino acid histidine is able to selectively decrease miR-372 levels in gastric adenocarcinoma (AGS) cells and to restore the expression of the target LATS2 protein. This activity led to the inhibition of proliferation of these cells. The study of the interactions of 4b with pre-miR-372 allowed for the elucidation of the molecular mechanism of the conjugate, thus leading to new perspectives for the design of future inhibitors.
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Aminoácidos/química , Carcinogênese , MicroRNAs/biossíntese , Neomicina/química , Neomicina/farmacologia , Purinas/química , Pirimidinas/química , Adenocarcinoma/patologia , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , MicroRNAs/genética , Simulação de Acoplamento Molecular , Neomicina/metabolismo , Conformação de Ácido Nucleico , Neoplasias Gástricas/patologiaRESUMO
MicroRNAs (miRNAs) are a recently discovered category of small RNA molecules that regulate gene expression at the post-transcriptional level. Accumulating evidence indicates that miRNAs are aberrantly expressed in a variety of human cancers and that the inhibition of these oncogenic miRNAs could find application in the therapy of different types of cancer. Herein, we describe the synthesis and biological evaluation of new small-molecule drugs that target oncogenic miRNAs production. In particular, we chose to target two miRNAs (i.e., miRNA-372 and -373) implicated in various types of cancer, such as gastric cancer. Their precursors (pre-miRNAs) are overexpressed in cancer cells and lead to mature miRNAs after cleavage of their stem-loop structure by the enzyme Dicer in the cytoplasm. Some of the newly synthesized conjugates can inhibit Dicer processing of the targeted pre-miRNAs in vitro with increased efficacy relative to our previous results (D.D. Vo et al., ACS Chem. Biol. 2014, 9, 711-721) and, more importantly, to inhibit proliferations of adenocarcinoma gastric cancer (AGS) cells overexpressing these miRNAs, thus representing promising leads for future drug development.
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Aminoglicosídeos/química , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Neoplasias Gástricas/química , Evolução Biológica , Sistemas de Liberação de Medicamentos , Humanos , MicroRNAs/química , Modelos Moleculares , Nebramicina/análogos & derivados , Nebramicina/química , Neomicina/química , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/patologia , Relação Estrutura-AtividadeRESUMO
MicroRNAs (miRNAs) are non-coding RNAs that regulate gene expression at the post-transcriptional level. It is now well established that the overexpression of some miRNAs (oncogenic miRNAs) is responsible for initiation and progression of human cancers and the discovery of new molecules able to interfere with their production and/or function represents one of the most important challenges of current medicinal chemistry of RNA ligands. In this work, we studied the ability of 18 different antibiotics, known as prokaryotic ribosomal RNA, to bind to oncogenic miRNA precursors (stem-loop structured pre-miRNAs) in order to inhibit miRNAs production. In vitro inhibition, binding constants, thermodynamic parameters and binding sites were investigated and highlighted that aminoglycosides and tetracyclines represent interesting pre-miRNA ligands with the ability to inhibit Dicer processing.
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Aminoglicosídeos/química , Aminoglicosídeos/farmacologia , Antibacterianos/química , Antibacterianos/farmacologia , MicroRNAs/genética , Tetraciclinas/química , Tetraciclinas/farmacologia , Sequência de Bases , RNA Helicases DEAD-box/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Modelos Moleculares , Dados de Sequência Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Ribonuclease III/genética , Ribossomos/efeitos dos fármacos , Ribossomos/genéticaRESUMO
The human immunodeficiency virus type-1 (HIV-1) Tat protein stimulates transcriptional elongation. Tat is involved in the transcription machinery by binding to the transactivation response region (TAR) RNA stem-loop structure, which is encoded by the 5' leader sequence found in all HIV-1 mRNAs. Herein, we report the rational design, synthesis, and in vitro evaluation of new RNA binding agents that were conceived in order to bind strongly and selectively to the stem-loop structure of TAR RNA and, thus, inhibit the Tat/TAR interaction. We have demonstrated that the conjugation of modified nucleobases, able to interact specifically with an RNA base pair, and various amino acids allows these motifs to bind the target RNA selectively and in a cooperative manner that leads to the inhibition of viral replication in HIV-infected cells.
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Aminoácidos/química , Aminoácidos/farmacologia , Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Produtos do Gene tat/metabolismo , HIV-1/efeitos dos fármacos , RNA/metabolismo , Sequência de Bases , Linhagem Celular , Infecções por HIV/tratamento farmacológico , HIV-1/fisiologia , Humanos , Purinas/química , Purinas/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , RNA/química , Replicação Viral/efeitos dos fármacosRESUMO
Guest Editors Ruth Brenk, Peng Wu and Maria Duca introduce the RSC Medicinal Chemistry themed collection on 'Targeting RNA with small molecules'.
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The French Society of Medicinal Chemistry or " Société de Chimie Thérapeutique " (SCT) was founded in 1966. Since its inception, its mission has been to promote knowledge in the main fields of pharmaceutical research and development, in particular the research and validation of biological targets of therapeutic interest, the screening, design and optimization of drug candidates, chemical biology, medicinal chemistry, pharmacokinetics, metabolism and toxicity. Since 1964, the Society has organized an annual international congress (RICT), and later thematic days for young researchers and workshops on specific topics. The SCT is also a member of the European Federation for Medicinal Chemistry (EFMC) and organized the International Symposium on Medicinal Chemistry (ISMC) in Nice in 2022. Several new trends can be identified in the activities of the SCT, such as the organization of regular webinars, but also the recent creation of the Young MedChem Forum, as well as the distribution of a newsletter reporting scientific achievements in the French community and abroad, and an improved presence on social networks. These trends are in line with the current changes in the field in terms of scientific progress, means of communication in the community and with the public and inclusiveness.
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The development of innovative methodologies to identify RNA binders has attracted enormous attention in chemical biology and drug discovery. Although antibiotics targeting bacterial ribosomal RNA have been on the market for decades, the renewed interest in RNA targeting reflects the need to better understand complex intracellular processes involving RNA. In this context, small molecules are privileged tools used to explore the biological functions of RNA and to validate RNAs as therapeutic targets, and they eventually are to become new drugs. Despite recent progress, the rational design of specific RNA binders requires a better understanding of the interactions which occur with the RNA target to reach the desired biological response. In this Review, we discuss the challenges to approaching this underexplored chemical space, together with recent strategies to bind, interact and affect biologically relevant RNAs.
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Descoberta de Drogas , RNA Ribossômico , RNA Ribossômico/genética , Descoberta de Drogas/métodos , RNA Bacteriano/genética , Antibacterianos/farmacologiaRESUMO
Noncoding RNAs (ncRNAs) play pivotal roles in the regulation of gene expression and represent a promising target for the development of new therapeutic approaches. Among these ncRNAs, microRNAs (miRNAs or miRs) are involved in the regulation of gene expression, and their dysregulation has been linked to several diseases such as cancers. Indeed, oncogenic miRNAs are overexpressed in cancer cells, thus promoting tumorigenesis and maintenance of cancer stem cells that are resistant to chemotherapy and often responsible for therapeutic failure. Here, we describe the design and synthesis of new small-molecule RNA binders able to inhibit the biogenesis of oncogenic miRNAs and target efficiently cancer stem cells. Through the biochemical study of their interaction with the target and thanks to intracellular assays, we describe the structure-activity relationships for this new series of RNA ligands, and we identify compounds bearing a very promising antiproliferative activity against cancer stem cells.
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MicroRNAs , Neoplasias , Humanos , MicroRNAs/metabolismo , Bleomicina , Ligantes , Neoplasias/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
Topoisomerase IB controls DNA topology by cleaving DNA transiently. This property is used by inhibitors, such as camptothecin, that stabilize, by inhibiting the religation step, the cleavage complex, in which the enzyme is covalently attached to the 3'-phosphate of the cleaved DNA strand. These drugs are used in clinics as antitumor agents. Because three-dimensional structural studies have shown that camptothecin derivatives act as base pair mimics and intercalate between two base pairs in the ternary DNA-topoisomerase-inhibitor complex, we hypothesized that base pairs mimics could act like campthotecin and inhibit the religation reaction after the formation of the topoisomerase I-DNA cleavage complex. We show here that three base pair mimics, nucleobases analogues of the aminophenyl-thiazole family, once targeted specifically to a DNA sequence were potent topoisomerase IB inhibitors. The targeting was achieved through covalent linkage to a sequence-specific DNA ligand, a triplex-forming oligonucleotide, and was necessary to position and keep the nucleobase analogue in the cleavage complex. In the absence of triplex formation, only a weak binding to the DNA and topoisomerase I-mediated DNA cleavage was observed. The three compounds were equally active once conjugated, implying that the intercalation of the nucleobase upon triplex formation is the essential feature for the inhibition activity.
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DNA Topoisomerases Tipo I/metabolismo , DNA/farmacologia , Marcação de Genes , Mimetismo Molecular , Ácidos Nucleicos Heteroduplexes/farmacologia , Inibidores da Topoisomerase I/farmacologia , Pareamento de Bases/efeitos dos fármacos , Pareamento de Bases/genética , Sequência de Bases , DNA/síntese química , Dano ao DNA/efeitos dos fármacos , Dano ao DNA/genética , Pegada de DNA/métodos , DNA Topoisomerases Tipo I/química , DNA Topoisomerases Tipo I/genética , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Desoxirribonuclease I/química , Desoxirribonuclease I/genética , Marcação de Genes/métodos , Mimetismo Molecular/genética , Dados de Sequência Molecular , Conformação de Ácido Nucleico/efeitos dos fármacos , Ácidos Nucleicos Heteroduplexes/síntese química , Inibidores da Topoisomerase I/síntese químicaRESUMO
Targeting RNA with synthetic small molecules attracted much interest during recent years as a particularly promising therapeutic approach in a large number of pathologies spanning from genetic disorders, cancers as well as bacterial and viral infections. In this work, we took advantage of a known RNA binder, neomycin, to prepare neomycin-imidazole conjugates mimicking the active site of ribonuclease enzymes able to induce a site-specific cleavage of HIV-1 TAR RNA in physiological conditions. These new conjugates were prepared using a straightforward synthetic methodology and were studied for their ability to bind the target, inhibit Tat/TAR interaction and induce selective cleavage using fluorescence-based assays and molecular docking. We found compounds with nanomolar affinity, promising cleavage activity and the ability to inhibit Tat/TAR interaction with submicromolar IC50 s.
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Repetição Terminal Longa de HIV , Neomicina , Neomicina/farmacologia , Neomicina/química , Neomicina/metabolismo , Clivagem do RNA , Simulação de Acoplamento Molecular , RNA Viral/química , RNA Viral/metabolismo , ImidazóisRESUMO
The discovery of new original scaffolds for selective RNA targeting is one of the main challenges of current medicinal chemistry since therapeutically relevant RNAs represent potential targets for a number of pathologies. Recent efforts have been devoted to the search for RNA ligands targeting the biogenesis of oncogenic miRNAs whose overexpression has been directly linked to the development of various cancers. In this work, we developed a new series of RNA ligands for the targeting of oncogenic miRNA biogenesis based on the 2-deoxystreptamine scaffold. The latter is part of the aminoglycoside neomycin and is known to play an essential role in the RNA interaction of this class of RNA binders. 2-deoxystreptamine was thus conjugated to natural and artificial nucleobases to obtain new binders of the oncogenic miR-372 precursor (pre-miR-372). We identified some conjugates exhibiting a similar biological activity to previously synthesized neomycin analogs and studied their mode of binding with the target pre-miR-372.
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Etoposide is a widely prescribed anticancer drug that stabilizes covalent topoisomerase II-cleaved DNA complexes. The drug contains a polycyclic ring system (rings A-D), a glycosidic moiety at C4, and a pendant ring (E-ring) at C1. Interactions between human topoisomerase IIα and etoposide in the binary enzyme--drug complex appear to be mediated by substituents on the A-, B-, and E-rings of etoposide. These protein--drug contacts in the binary complex have predictive value for the actions of etoposide within the ternary topoisomerase IIα--drug--DNA complex. Although the D-ring of etoposide does not appear to contact topoisomerase IIα in the binary complex, etoposide derivatives with modified D-rings display reduced cytotoxicity against murine leukemia cells [Meresse, P., et al. (2003) Bioorg. Med. Chem. Lett. 13, 4107]. This finding suggests that alterations in the D-ring may affect etoposide activity toward topoisomerase IIα in the ternary enzyme--drug--DNA complex. Therefore, to address the potential contributions of the D-ring to the activity of etoposide, we characterized drug derivatives in which the C13 carbonyl was moved to the C11 position (retroetoposide and retroDEPT) or the D-ring was opened (D-ring diol). All of the D-ring alterations decreased the ability of etoposide to enhance DNA cleavage mediated by human topoisomerase IIα in vitro and in cultured cells. They also weakened etoposide binding in the ternary enzyme--drug--DNA complex and altered sites of enzyme-mediated DNA cleavage. On the basis of these findings, we propose that the D-ring of etoposide has important interactions with DNA in the ternary topoisomerase II cleavage complex.
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Antígenos de Neoplasias/química , Antineoplásicos Fitogênicos/química , DNA Topoisomerases Tipo II/química , Proteínas de Ligação a DNA/química , DNA/química , Etoposídeo/química , Antígenos de Neoplasias/metabolismo , Antineoplásicos Fitogênicos/metabolismo , Linhagem Celular Tumoral , DNA/metabolismo , Clivagem do DNA , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Interações Medicamentosas , Etoposídeo/metabolismo , Humanos , Saccharomyces cerevisiae/metabolismoRESUMO
At least one bisaminoacyl-tRNA is synthesized in nature (by Thermus thermophilus phenylalanyl-tRNA synthetase), and many disubstituted tRNAs have been prepared in vitro. Such misacylated tRNAs are able to participate in protein synthesis, even though they lack the free 2'-OH group of the 3'-terminal adenosine moiety. Their ready participation in protein synthesis implies significant chemical reactivity. The basis for this reactivity has been documented previously. Surprisingly, the aminoacyl moieties of these tRNAs also exhibit exceptional chemical stability. In the present report, bisaminoacylated nucleotides are investigated computationally and experimentally to define the basis for the stability of such species. Molecular modeling of bisalanyl-AMP in the absence of solvent and in the presence of a limited number of water molecules revealed two common features among the low-energy structures. The first was the presence of H-bonding interactions between the two aminoacyl moieties. The second was the presence of a H-bonding interaction between the 2'-O-alanyl moiety and the N-3 atom of the adenine nucleobase, typically mediated through a water molecule. The prediction of an interaction between an aminoacyl moiety and the adenine nucleobase was confirmed experimentally by comparing the behavior of bisalanyl-AMP and bisalanyl-UMP in the presence of model nucleophiles. This study suggests a possible role for the adenosine moiety at the 3'-end of aminoanyl-tRNAs in controlling the stability and reactivity of the aminoacyl moiety and has important implications for the reactivity and stability of normal aminoacyl-tRNAs.
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Nucleotídeos/química , RNA de Transferência/química , Monofosfato de Adenosina/análogos & derivados , Ligação de Hidrogênio , Modelos Moleculares , Estabilidade de RNA , Aminoacilação de RNA de Transferência , Uridina Monofosfato/análogos & derivadosRESUMO
This review, divided into three sections, describes the contribution of the chemists' community to the development and application of triple helix strategy by using artificial nucleic acids, particularly for the recognition of DNA sequences incorporating base pair inversions. Firstly, the development of nucleobases that recognise CG inversion is surveyed followed secondly by specific recognition of TA inverted base pair. Finally, we point out in the last section recent perspectives and applications, driven from knowledge in nucleic acids interactions, in the growing field of nanotechnology and supramolecular chemistry at the border area of physics, chemistry and molecular biology.
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Pareamento Incorreto de Bases , DNA/química , Carboidratos/química , Ligação de Hidrogênio , Conformação de Ácido Nucleico , Oligonucleotídeos/químicaRESUMO
Despite the existing arsenal of anti-cancer drugs, 10 million people die each year worldwide due to cancers; this highlights the need to discover new therapies based on innovative modes of action against these pathologies. Current chemotherapies are based on the use of cytotoxic agents, targeted drugs, monoclonal antibodies or immunotherapies that are able to reduce or stop the proliferation of cancer cells. However, tumor eradication is often hampered by the presence of resistant cells called cancer stem-like cells or cancer stem cells (CSCs). Several strategies have been proposed to specifically target CSCs such as the use of CSC-specific antibodies, small molecules able to target CSC signaling pathways or drugs able to induce CSC differentiation rendering them sensitive to classical chemotherapy. These latter compounds are the focus of the present review, which aims to report recent advances in anticancer-differentiation strategies. This therapeutic approach was shown to be particularly promising for eradicating tumors in which CSCs are the main reason for therapeutic failure. This general view of the chemistry and mechanism of action of compounds inducing the differentiation of CSCs could be particularly useful for a broad range of researchers working in the field of anticancer therapies as the combination of compounds that induce differentiation with classical chemotherapy could represent a successful approach for future therapeutic applications.