Drug discovery articles within Nature Communications

Featured

  • Article
    | Open Access

    Polypharmacology drugs are compounds designed to inhibit multiple protein targets. Here, authors use recent advances in AI to rapidly generate polypharmacology compounds against any pair of protein targets, experimentally validating numerous compounds targeting MEK1 and mTOR.

    • Brenton P. Munson
    • , Michael Chen
    •  & Trey Ideker

  • Article
    | Open Access

    In this study, the authors engineered a targeted Saccharomyces boulardii probiotic yeast platform, showing it exhibits high adherence to extracellular matrix proteins, resulting in longer gut residence, higher colon concentrations, and enhanced recovery in murine colitis.

    • Mairead K. Heavey
    • , Anthony Hazelton
    •  & Juliane Nguyen

  • Article
    | Open Access

    Galectin-3, mainly produced and secreted by macrophages, is elevated in diabetes. Here, the authors show that galectin-3 directly interacts with voltage-gated channel auxiliary subunit gamma 1 (CACNG1) and blocks calcium transients and subsequent insulin secretion.

    • Qian Jiang
    • , Qijin Zhao
    •  & Pingping Li

  • Article
    | Open Access

    Circulating proteins are a potential source of cancer biomarkers. Here, the authors assessed 2,074 circulating proteins and used Mendelian randomisation to compare with the risk of 9 common cancer types across multiple GWAS cohorts and identified key considerations with respect to the potential for adverse effects of altering cancer-risk proteins that inform their utility in cancer prevention.

    • Karl Smith-Byrne
    • , Åsa Hedman
    •  & Anders Mälarstig

  • Article
    | Open Access

    The differential effects of targeting individual domains of multidomain enzymatic proteins are generally poorly understood. Here, the authors demonstrate lineage-specific sensitivities to domain-specific inhibition of EP300/CBP proteins across cancer and link these effects in group 3 medulloblastoma to control of a transcriptional dependency network.

    • Noha A. M. Shendy
    • , Melissa Bikowitz
    •  & Adam D. Durbin

  • Article
    | Open Access

    The use of data-driven generative models for drug design is challenging due to the scarcity of data. Here, the authors introduce a “zero-shot" generative deep model to enable the generation of molecules by both structure- and ligand-based drug design and apply it to design PPARγ agonists with desired properties.

    • Kenneth Atz
    • , Leandro Cotos
    •  & Gisbert Schneider

  • Article
    | Open Access

    Installation of small aliphatic motifs within pharmaceuticals provides a medicinally relevant tool in drug discovery programmes. Here, the authors report a late-stage meta-C–H alkylation method facilitating the biological properties modulation of therapeutic agents.

    • Lucas Guillemard
    • , Lutz Ackermann
    •  & Magnus J. Johansson

  • Article
    | Open Access

    Ligand discovery against membrane proteins has been a major challenge, mainly due to the peculiar nature of their natural habitat. Here, the authors designed a new chemical proteomic probe that targets the lysines exposed on the cell surface and developed a chemical proteomic strategy for global analysis of surface functionality in living cells.

    • Ting Wang
    • , Shiyun Ma
    •  & Haojie Lu

  • Article
    | Open Access

    CRISPR-Cas13a based methods currently use contiguous target RNA activation, which only enables single-target detection or editing. Here the authors propose a noncontiguous target RNA activation approach which can provide rapid, simultaneous and sensitive detection of two RNAs in a single readout, as well as parallel dual transgene knockdown.

    • Hongrui Zhao
    • , Yan Sheng
    •  & Jiaming Hu

  • Article
    | Open Access

    VISTA is a pH-dependent inhibitory checkpoint for T-cells that is abundant on myeloid lineage cells and antagonists of VISTA may successfully reinvigorate anti-tumour immunity. Here, the authors show that the antibody SNS-101, which is currently being investigated in humans in a clinical trial, is characterized by pH-sensitivity that endows it with favorable pharmacokinetic and safety profiles, and enhanced therapeutic effect when combined with PD-1 checkpoint inhibitors.

    • Thomas Thisted
    • , F. Donelson Smith
    •  & Edward H. van der Horst

  • Article
    | Open Access

    In non-small cell lung cancer (NSCLC), inactivating p53 mutations can drive resistance to cisplatin. Here, the authors develop fluplatin nanoparticles comprising a prodrug of cisplatin and fluvastin (mutant p53 inhibitor) which selectively degrades mutant p53, prevent tumor recurrences in preclinical models of p53 mutant NSCLC.

    • Yu-Yang Bi
    • , Qiu Chen
    •  & Hu-Lin Jiang

  • Article
    | Open Access

    The natural hallucinogen psilocybin — produced by so-called magic mushrooms — holds promise for the treatment of depression and other mental health conditions. Here, the authors provide a structural and biochemical analysis of the Psilocybe methyl transferase PsiM that provides mechanistic insight into the last step of psilocybin biosynthesis.

    • Jesse Hudspeth
    • , Kai Rogge
    •  & Sebastiaan Werten

  • Article
    | Open Access

    Lysosomal storage disorders (LSDs) are severe genetic diseases currently without routine therapies. Here, the authors identified that SNX8 participates in lysosome reformation and serves as a potential drug target for new therapies to treat LSDs.

    • Xinran Li
    • , Cong Xiang
    •  & Xin-Hua Feng

  • Article
    | Open Access

    To promote the development of effective small molecule modulators that may help treat diverse neuropsychiatric disorders, this study elucidates the mechanism of a specific positive modulator of neuronal potassium channels at near-atomic resolution.

    • Qiansheng Liang
    • , Gamma Chi
    •  & Manuel Covarrubias

  • Article
    | Open Access

    The filamentous fungus expression system Thermothelomyces heterothallica (C1) is a protein expression system that may be useful for large scale antibody production. Here the authors characterise the production of a human monoclonal antibody that neutralises SARS-CoV-2 and compare functional properties in vitro and in animal models to antibodies produced using other methods.

    • Franziska K. Kaiser
    • , Mariana Gonzalez Hernandez
    •  & Albert D.M.E. Osterhaus

  • Article
    | Open Access

    Antimicrobial resistance is a global health threat and the development of alternative strategies to overcome it is of high interest. Here, the authors report proteolysis targeting chimeras active in bacteria (BacPROTACs) that bind to ClpC1, a component of the mycobacterial protein degradation machinery, and apply them for targeting a range of mycobacterial strains, including antibiotic-resistant ones.

    • Lukas Junk
    • , Volker M. Schmiedel
    •  & Guido Boehmelt

  • Article
    | Open Access

    G protein responses mediated by GPCRs may differ depending on their environment. Here, using highly sensitive Gi/o sensors, the authors reveal the specific pharmacological and Gi/o protein responses of some native GPCRs in neurons, and the influence of G protein composition.

    • Chanjuan Xu
    • , Yiwei Zhou
    •  & Jianfeng Liu

  • Article
    | Open Access

    All natural AAV serotypes transduce murine hepatocytes more efficiently than their human counterparts in human liver chimeric mouse models. Here the authors developed a novel humanized mouse were human transduction of AAV can be studied.

    • Mercedes Barzi
    • , Tong Chen
    •  & Karl-Dimiter Bissig

  • Article
    | Open Access

    Two small-molecule drugs, risdiplam and branaplam, have been developed for treating spinal muscular atrophy. Here the authors develop quantitative modeling methods for the sequence-specific and concentration-dependent effects of these and other splice-modifying drugs.

    • Yuma Ishigami
    • , Mandy S. Wong
    •  & Justin B. Kinney

  • Article
    | Open Access

    Large-scale OMICs investigations of biological systems can be used to predict functional relationships between compounds, genes and proteins. Here, the authors develop a deep learning-based approach that significantly increases the number of high-quality compound-target predictions relative to existing methods.

    • Hao Chen
    • , Frederick J. King
    •  & Yingyao Zhou

  • Perspective
    | Open Access

    The development of human cellular models of aging that surpass the limitations of animal models of aging is urgent. Here, the authors explore the opportunities and limitations of cellular reprogramming to create reliable aging in vitro models and their potential for the discovery of anti-aging compounds.

    • Patricia R. Pitrez
    • , Luis M. Monteiro
    •  & Lino Ferreira

  • Article
    | Open Access

    HFpEF has few effective treatments. Here, the authors show that inhibition of histone deacetylase 6 (HDAC6) with TYA-018 reverses established HFpEF symptoms in mice, comparably to the use of a sodium-glucose cotransporter 2 inhibitor; highlighting HDAC6 as a potential target to treat HFpEF.

    • Sara Ranjbarvaziri
    • , Aliya Zeng
    •  & Jin Yang

  • Article
    | Open Access

    The T cell receptor β-chain is expressed in two isoforms, TRBC1 and TRBC2, with clonally expanded mature T cell lymphomas expressing one of them exclusively, while healthy T cells randomly express either TRBC1 or TRBC2. Here authors show structure-based design of a TRBC2-specific antibody, and depletion of malignant T cells carrying TRBC1 or TRBC2 with CAR-T cells against the cognate receptor chain in murine models.

    • Mathieu Ferrari
    • , Matteo Righi
    •  & Martin Pule

  • Article
    | Open Access

    Assessing cell phenotypes in image-based assays requires solid computational methods for transforming images into quantitative data. Here, the authors present a strategy for learning representations of treatment effects from high-throughput imaging, following a causal interpretation.

    • Nikita Moshkov
    • , Michael Bornholdt
    •  & Juan C. Caicedo

  • Article
    | Open Access

    Limited tumor cell delivery is a major challenge for the efficacious delivery of siRNAs to silence traditionally undruggable oncogenes. Here the authors optimize siRNAs for in situ binding to albumin through C18 lipid modifications and show the application of the lead conjugate structure for targeting MCL1 in orthotopic breast tumors in mice.

    • Ella N. Hoogenboezem
    • , Shrusti S. Patel
    •  & Craig L. Duvall

  • Article
    | Open Access

    In Acute Myeloid Leukemia a population of quiescent leukemic stem cells (LSCs) evade chemotherapy and initiate relapse, but what makes them grow again is unknown. Here, the authors show (i) that LSCs hijack ectopic signaling pathways to kick-start their growth and (ii) that growth can be blocked with repurposed drugs in t(8;21) AML sub-type.

    • Sophie G. Kellaway
    • , Sandeep Potluri
    •  & Constanze Bonifer

  • Article
    | Open Access

    Here the authors develop perfusable inner blood-retinal barrier-specific microvascular networks with human primary retinal microvascular cells. They show that chronic diabetic stimulation leads to the generation of early hallmarks of diabetic retinopathy, including pericyte and capillary dropout, ghost vessels, and inflammation.

    • Thomas L. Maurissen
    • , Alena J. Spielmann
    •  & Héloïse Ragelle

  • Article
    | Open Access

    GPR34 is a GPCR which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative endogenous ligand. Here, authors report two cryo-EM structures of human GPR34-Gi complex with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or its derivative M1.

    • Tamaki Izume
    • , Ryo Kawahara
    •  & Osamu Nureki

  • Article
    | Open Access

    The dynamic protein corona hinders the uptake of nanocarriers in desired target cell populations, limiting their bench-to-bedside translation. Here the authors reveal that the modification of hydroxyl and amino functional groups on nanovesicles can rationally regulate the composition of protein coronas to improve the efficiency of targeted drug delivery.

    • Yunqiu Miao
    • , Lijun Li
    •  & Yong Gan

  • Article
    | Open Access

    In this work, the authors report the use of a computationally and rationally designed self-assembling peptide that has robust antiviral capability with demonstrated specificity in binding to SARS-CoV-2 and inhibition of viral entry into human cells.

    • Joseph Dodd-o
    • , Abhishek Roy
    •  & Vivek Kumar

  • Article
    | Open Access

    Obesity is a risk factor for diseases. Here, authors found that inhibition of cyclin-dependent kinase 6 increased de novo lipogenesis in the adipose tissues but not in the liver, which may provide a strategy to concur obesity-induced maladies.

    • Alexander J. Hu
    • , Wei Li
    •  & Miaofen G. Hu

  • Article
    | Open Access

    Obesity is a global health challenge with an ongoing need for new medical treatments. Here, the authors show that artesunate, an FDA-approved treatment for severe malaria, can be repurposed for the treatment of obesity via GDF15/GFRAL signaling axis without overt side effects in mice and non-human primates.

    • Xuanming Guo
    • , Pallavi Asthana
    •  & Hoi Leong Xavier Wong

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