Featured
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Article
| Open Access
Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer’s disease
To advance our understanding of pathological features associated with Alzheimer’s disease (AD), chemical tools with distinct specificity towards AD targets would be valuable. Here the authors used a structure-mechanism-based design strategy to obtain small molecules as chemical regulators for distinct pathological factors linked to AD pathology.
- Michael W. Beck
- , Jeffrey S. Derrick
- & Mi Hee Lim
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Article
| Open Access
Drug design from the cryptic inhibitor envelope
The conformational dynamics of a compound has a large effect on ligand/receptor binding. Here, the authors employ NMR spectroscopy to study ligand binding to the enzyme LpxC, discovering an inhibitor envelope that was not identifiable by crystallography and subsequently developing a highly potent inhibitor.
- Chul-Jin Lee
- , Xiaofei Liang
- & Pei Zhou
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De novo branching cascades for structural and functional diversity in small molecules
Generating diverse structures with a minimum amount of synthetic effort is an important goal for drug discovery. Here, the authors report a two-phase synthesis for the generation of skeletally diverse small molecules—forming molecular scaffolds and subsequently diversifying each into multiple structures.
- Miguel Garcia-Castro
- , Lea Kremer
- & Kamal Kumar
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Suppression of the FOXM1 transcriptional programme via novel small molecule inhibition
Overexpression of the FOXM1 transcription factor occurs in several cancer and correlates with poor prognoses. Here, the authors identify a novel small molecule capable of displacing FOXM1 from its DNA consensus motif in vitro, displace it from target promoters and downregulate the expression of its target genes cancer cells.
- Michael V. Gormally
- , Thomas S. Dexheimer
- & Shankar Balasubramanian
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Small-molecule Bax agonists for cancer therapy
A major proapoptotic mediator, Bax, is expressed in lung cancer and its activity can be regulated by phosphorylation. Here, the authors screen a library of compounds for their ability to alter the phosphorylation status of Bax and identify therapeutic candidates.
- Meiguo Xin
- , Rui Li
- & Xingming Deng
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Article |
A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV
Mucolipidosis type IV is a lysosomal storage disorder caused by mutations in the endolysosomal cation channel TRPML1 and results in progressive neurodegeneration. Here, Chen et al. demonstrate that small molecules can be used to restore TRPML1 mutant channel function and rescue disease-associated symptoms.
- Cheng-Chang Chen
- , Marco Keller
- & Christian Grimm
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Article |
Downsizing a human inflammatory protein to a small molecule with equal potency and functionality
Replicating the functionality of bioactive proteins using rationally designed small molecule mimics is both economically valuable and synthetically challenging. Here the authors develop a mimic of the inflammatory protein C3a with equal biological potency but enhanced stability and bioavailability.
- Robert C. Reid
- , Mei-Kwan Yau
- & David P. Fairlie
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Disrupting malaria parasite AMA1–RON2 interaction with a small molecule prevents erythrocyte invasion
Invasion of host erythrocytes is an essential step in the life cycle of P. falciparum. Srinivasan et al.demonstrate that small-molecule inhibitors can block the entry of the parasite into erythrocytes, highlighting the potential of invasion inhibitors as antimalarials.
- Prakash Srinivasan
- , Adam Yasgar
- & Louis H. Miller
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Article |
Small molecules enable neurogenin 2 to efficiently convert human fibroblasts into cholinergic neurons
Human non-neuronal somatic cells can be converted into neurons; however, this is a low-efficiency process and the resulting neuronal subtypes are of low purity. Here the authors show that two small molecules enable NGN2 to efficiently convert human fibroblasts into pure cholinergic neurons.
- Meng-Lu Liu
- , Tong Zang
- & Chun-Li Zhang
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Article |
Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules
Myotonic dystrophy type 1 (DM1) is caused by defects in the alternative splicing of pre-mRNA. Childs-Disney and colleagues report two small molecules that either induce or reverse DM1-associated splicing defects by modulating the binding of pre-mRNA to muscleblind-like 1 protein.
- Jessica L. Childs-Disney
- , Ewa Stepniak-Konieczna
- & Matthew D. Disney
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Identification and optimization of small-molecule agonists of the human relaxin hormone receptor RXFP1
The peptide hormone relaxin has potential in the treatment of acute heart failure, but it must be intravenously injected and has a short half-life after administration. Now, small-molecule alternatives to relaxin are reported with similar efficacies to the natural hormone in functional assays.
- Jingbo Xiao
- , Zaohua Huang
- & Juan J. Marugan
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Article
| Open Access
Assembly of a π–π stack of ligands in the binding site of an acetylcholine-binding protein
AChBP is used as a structurally accessible prototype for studying ligand binding to nicotinic acetylcholine receptors. Stornaiuolo et al. report that a small molecule binds AChBP in an ordered p–p stack of three molecules per binding site, which may lead to new approaches in drug design.
- Mariano Stornaiuolo
- , Gerdien E. De Kloe
- & Titia K. Sixma
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Identifying the preferred RNA motifs and chemotypes that interact by probing millions of combinations
Identifying molecules that bind to RNA is difficult because information about RNA–ligand interactions is limited. Tran and Disney report a solution-based screening method that can probe large numbers of RNA motif-small molecule interactions to identify privileged RNA structures and chemical spaces that interact.
- Tuan Tran
- & Matthew D. Disney
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Article
| Open Access
A kinase inhibitor screen identifies small-molecule enhancers of reprogramming and iPS cell generation
The efficiency of reprogramming somatic cells to induced pluripotent stem cells is low. To enhance reprogramming efficiency, Li and Rana used a chemical screen and identified several kinase inhibitors that enhance reprogramming, and show that blocking Aurora A, p38 and inositiol triphosphate 3-kinase signalling is important for this process.
- Zhonghan Li
- & Tariq M. Rana
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Imaging enzyme-triggered self-assembly of small molecules inside live cells
Supramolecular interactions allow some small molecules to self-assemble into nanofibres and hydrogels in aqueous environments. Gaoet al.report a hydrogelator that forms fluorescent nanofibres within cells, leading to the visualization of their self-assembly at the endoplasmic reticulum.
- Yuan Gao
- , Junfeng Shi
- & Bing Xu
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Article
| Open Access
An intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid
β-Catenin can be oncogenic but finding inhibitors has been a challenge. Here, five compounds are identified, which attenuate transcriptional β-catenin outputs in colorectal cancer cells, and the response to one of them is shown to require an intrinsically labile α-helix next to the BCL9-binding site in β-catenin.
- Marc de la Roche
- , Trevor J. Rutherford
- & Mariann Bienz
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Review Article |
Diversity-oriented synthesis as a tool for the discovery of novel biologically active small molecules
Biologically active molecules can be identified through the screening of small-molecule libraries, but compound collections typically consist of large numbers of structurally similar compounds. Gallowayet al. review how diversity-oriented synthesis can efficiently generate structurally diverse compound libraries.
- Warren R.J.D. Galloway
- , Albert Isidro-Llobet
- & David R. Spring
Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition