Drug discovery

  • Article
    | Open Access

    Prioritising genes as potential drug targets is challenging and often unsuccessful once testing efficacy in humans. Here, the authors propose an approach to identifying drug targets that uses evidence from gain- or loss-of-function mutations associated with bidirectional effects on phenotypes.

    • Karol Estrada
    • , Steven Froelich
    •  & Lon R. Cardon
  • Article
    | Open Access

    The mechanism by which parathyroid hormone mediates the switch from bone resorption to bone formation is unclear. Here, the authors show that SLPI regulates the communication between osteoblasts and osteoclasts to promote the anabolic effect of parathyroid hormone.

    • Akito Morimoto
    • , Junichi Kikuta
    •  & Masaru Ishii
  • Article
    | Open Access

    Bafilomycin A1, a member of macrolide antibiotics and an autophagy inhibitor, serves as a specific and potent V-ATPases inhibitor. Here authors report the cryo-EM structure of bafilomycin A1-bound V-ATPase with six bafilomycin A1 molecules bound to the c-ring and reveal the molecular basis for Bafilomycin A1 inhibition of the V-ATPase.

    • Rong Wang
    • , Jin Wang
    •  & Xiaochun Li
  • Article
    | Open Access

    Antibodies targeting the spike protein of coronaviruses are potential candidates for therapeutic development. Here, Bertoglio et al. use phage display to select anti-SARS-CoV-2 spike antibodies from the human naïve universal antibody gene libraries HAL9/10 that block interaction with ACE2 receptor to inhibit infection.

    • Federico Bertoglio
    • , Doris Meier
    •  & Michael Hust
  • Article
    | Open Access

    The iRGD tumor-penetrating peptide can achieve tumor specific drug delivery but whether and how it can penetrate into desmoplastic tumors is unknown. Here, the authors show that β5 integrin expression on tumor cells, mediated by CAFs-derived TGF-β, is required for iRGD penetration into the desmoplastic PDAC microenvironment and that iRGD-based combination therapy is effective in PDAC mouse models.

    • Tatiana Hurtado de Mendoza
    • , Evangeline S. Mose
    •  & Kazuki N. Sugahara
  • Article
    | Open Access

    Until today effective antivirals for COVID-19 treatment are not widely available. Here, Zhao et al. characterize a dual-functional cross-linking peptide, 8P9R, that can inhibit SARS-CoV-2 virus entry in vitro and suppresses viral replication in vivo in golden Syrian hamster.

    • Hanjun Zhao
    • , Kelvin K. W. To
    •  & Kwok-Yung Yuen
  • Article
    | Open Access

    Epigenetic mechanisms associated with the differentiation state of cancer cells and their heterogeneity influence tumor responses to oncogene-targeted therapies. In this study, the authors perform an epigenetic compound screen and single-cell analysis in BRAF-mutant melanoma cells to identify compounds that block three distinct drug-tolerant epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET proteins.

    • Mehwish Khaliq
    • , Mohan Manikkam
    •  & Mohammad Fallahi-Sichani
  • Article
    | Open Access

    There is an unmet clinical need to identify therapeutic options for the treatment of pancreatic cancer (PDAC). Here the authors present a systematic screening approach for the identification of potential PDAC cell surface target candidates for CAR-T cell based immunotherapy, followed by their functional validation in preclinical models.

    • Daniel Schäfer
    • , Stefan Tomiuk
    •  & Olaf Hardt
  • Article
    | Open Access

    The BCL-2 family protein BAX functions to regulate mitochondria-driven cell death. Here the authors show that the drug Eltrombopag inhibits BAX and prevents apoptosis induced by cytotoxic stimuli.

    • Adam Z. Spitz
    • , Emmanouil Zacharioudakis
    •  & Evripidis Gavathiotis
  • Article
    | Open Access

    Molecular heterogeneity of acute myeloid leukaemia (AML) across patients is a major challenge for prognosis and therapy. Here, the authors show that NPM1 mutated AML is a heterogeneous class, consisting of two subtypes which exhibit distinct molecular characteristics, differentiation state, patient survival and drug response.

    • Arvind Singh Mer
    • , Emily M. Heath
    •  & Benjamin Haibe-Kains
  • Article
    | Open Access

    Glycolytic enzymes are challenging drug targets due to their highly conserved active sites and phosphorylated substrates. Here, the authors identify fast acting allosteric inhibitors of Trypanosoma brucei phosphofructokinase that block trypanosome glycolysis and provide cure evidence in murine model.

    • Iain W. McNae
    • , James Kinkead
    •  & Malcolm D. Walkinshaw
  • Article
    | Open Access

    Clinical trials of novel therapeutics for Alzheimer’s Disease (AD) have provided largely negative results, so far. Here, the authors present a machine learning framework that quantifies potential associations between the pathology of AD severity and gene-based molecular mechanisms to enable drug repurposing.

    • Steve Rodriguez
    • , Clemens Hug
    •  & Artem Sokolov
  • Article
    | Open Access

    The arginine methyltransferase PRMT5 is over-expressed in cancer and has a role in the maintenance of stem cells. Here, the authors show that PRMT5 inhibitors can block the growth of patient derived glioblastoma stem cell cultures in vitro and in vivo, suggesting that PRMT5 inhibition may be a useful therapeutic strategy

    • Patty Sachamitr
    • , Jolene C. Ho
    •  & Peter B. Dirks
  • Article
    | Open Access

    p53 mediates the response to irradiation, however, tissues with similar levels of p53 have different radiation sensitivities. Here, the authors show that the in vivo p53 dynamics varies in these tissues after radiation, and the use of Mdm2 inhibitor to sustain p53 activity enhances radiosensitivity.

    • Jacob Stewart-Ornstein
    • , Yoshiko Iwamoto
    •  & Galit Lahav
  • Article
    | Open Access

    C9orf72 expansion mutations are the most common genetic cause of ALS and FTD, which have limited therapies. The authors generate stereopure oligonucleotides that selectively deplete expansion-containing transcripts and protect against expansion-associated pathologies in preclinical models.

    • Yuanjing Liu
    • , Jean-Cosme Dodart
    •  & Robert H. Brown Jr.
  • Article
    | Open Access

    Macrophages may polarize into different states with distinct regulatory functions for inflammation. Here the authors perform high-throughput in vitro screening of a library of ~4000 compounds to identify those with specific effects on human macrophage polarization, while RNAseq helps uncover the targets and pathways mediating these effects.

    • Guangan Hu
    • , Yang Su
    •  & Jianzhu Chen
  • Article
    | Open Access

    Cellular models are needed to study disease in vitro and to screen drugs for toxicity and efficacy. Here the authors develop a bioprinting approach to transfer spheroids into self-healing support hydrogels at high resolution, which enables their patterning and fusion into high-cell density microtissues of prescribed spatial organization.

    • Andrew C. Daly
    • , Matthew D. Davidson
    •  & Jason A. Burdick
  • Article
    | Open Access

    Our understanding of the molecular mechanisms underlying pathological protein aggregation remains incomplete. Here, single molecule infrared nanospectroscopy (AFM-IR) offers insight into the structure of Aβ42 oligomeric and fibrillar species and their interaction with an aggregation inhibitor, paving the way for single molecule drug discovery studies.

    • Francesco Simone Ruggeri
    • , Johnny Habchi
    •  & Tuomas P. J. Knowles
  • Article
    | Open Access

    Bispecific antibodies can bind to two distinct targets though the fusion of two different Fv regions. In this study, the authors develop DutaFabs that present two separated and independent antigen binding sites within the same Fv region, giving rise to bispecific Fab fragments.

    • Roland Beckmann
    • , Kristian Jensen
    •  & Hubert Kettenberger
  • Article
    | Open Access

    Transdermal delivery has emerged as a preferred method of drug delivery. Here, the authors report on the application of porous polymer microneedles coupled with electroosmosis powered by enzymatic batteries for the transport of small and large molecules through the skin.

    • Shinya Kusama
    • , Kaito Sato
    •  & Matsuhiko Nishizawa
  • Article
    | Open Access

    Effective screening of drugs to treat amyloid oligomeric aggregates associated with Alzheimer’s is needed for drug development. Here the authors report on the creation of an amyloid corona around a plasmonic nanoparticle to monitor amyloid degradation when exposed to potential drugs and demonstrate application.

    • Dongtak Lee
    • , Dongsung Park
    •  & Dae Sung Yoon
  • Article
    | Open Access

    The SARS-CoV-2 papain-like protease (PLpro) is of interest as a drug target. Here, the authors identify GRL0617 as a PPI (protein–protein interaction) inhibitor of SARS-CoV-2 PLpro that inhibits its deISGylating activity and present the mechanism of action of the compound through the GRL0617-bound PLpro crystal structure and NMR studies.

    • Ziyang Fu
    • , Bin Huang
    •  & Hao Huang
  • Article
    | Open Access

    Mesenchymal stromal cells (MSCs) have been shown to support multiple myeloma (MM) development. Here, MSCs isolated from the bone marrow of MM patients are shown to have altered DNA methylation patterns and a methyltransferase inhibitor reverts MM-associated bone loss and reduces tumour burden in MM murine models.

    • Antonio Garcia-Gomez
    • , Tianlu Li
    •  & Esteban Ballestar
  • Article
    | Open Access

    Infection by Helicobacter pylori is associated with peptic ulcers and gastric cancer. H. pylori urease is required for colonization of the stomach and thus an attractive antimicrobial drug target. Cryo-EM analyses of the H. pylori urease with inhibitors bound reveal structural details useful in rational drug design.

    • Eva S. Cunha
    • , Xiaorui Chen
    •  & Hartmut Luecke
  • Article
    | Open Access

    Here, Reader et al. screen the Medicines for Malaria Venture Pandemic Response Box in parallel against Plasmodiumasexual and liver stage parasites, stage IV/V gametocytes, gametes, oocysts and as endectocides. They identify two potent transmission-blocking drugs: a histone demethylase inhibitor ML324 and the antitubercular SQ109.

    • Janette Reader
    • , Mariëtte E. van der Watt
    •  & Lyn-Marié Birkholtz
  • Review Article
    | Open Access

    Advances made in synthesis and analytical techniques has allowed the exploration and mimicry of natural materials. Resilin-mimetics have emerged from this advance as a biomaterial with a range of potential applications. Here, the authors review the history and current research on resilin-mimetics, providing a future perspective.

    • Rajkamal Balu
    • , Naba K. Dutta
    •  & Namita Roy Choudhury
  • Article
    | Open Access

    The bifunctional enzyme CoaBC catalyses the second and third step in the Coenzyme A (CoA) biosynthesis pathway and is of interest as a M. tuberculosis drug target. Here, the authors present the full-length crystal structure of Mycobacterium smegmatis CoaBC, which is regulated by CoA and CoA thioesters and forms a dodecamer and by performing a high-throughput screen they identify selective inhibitors of M. tuberculosis CoaB that bind to an allosteric site within CoaB.

    • Vitor Mendes
    • , Simon R. Green
    •  & Tom L. Blundell
  • Article
    | Open Access

    Unlike RORα, which has been thought to be somewhat redundant, RORγt has been well characterized in its function and contribution to the development of Th17 cells. Here the authors show that RORα is important in Th17 differentiation and that RORα deletion or a small molecule inhibitor of RORα can reduce disease in EAE and colitis mouse models.

    • Ran Wang
    • , Sean Campbell
    •  & Laura A. Solt
  • Perspective
    | Open Access

    Ketamine is associated with rapid antidepressant effects and temporary dissociative experiences, and this review examines whether these dissociative symptoms are necessary for antidepressant efficacy. Although the current literature does not support this relationship, further work is needed to explore possible associations at the molecular, biomarker, and psychological levels.

    • Elizabeth D. Ballard
    •  & Carlos A. Zarate Jr.
  • Article
    | Open Access

    Snakebite is a life-threatening neglected tropical disease that is currently treated using different antibody-based antivenoms, each effective against bites of specific snake species, but not others. Here, the authors show that a combination of two toxin-inhibiting repurposed drugs provides broad protection in experimental animals against the lethal effects of snakebites from multiple snake species.

    • Laura-Oana Albulescu
    • , Chunfang Xie
    •  & Nicholas R. Casewell
  • Article
    | Open Access

    Therapeutic angiogenesis has the potential of inducing and maintaining new blood vessels and thus improving outcomes in patients with ischemic disorders. Mannosamine functions as an endothelial cell mitogen/survival factor through activation of stress pathways and might be useful to protect and regenerate the vascular endothelium in a variety of disorders.

    • Cuiling Zhong
    • , Pin Li
    •  & Napoleone Ferrara
  • Article
    | Open Access

    The mecA gene confers resistance to many β-lactam antibiotics in community-associated MRSA bacteria. Here, Snitser et al. show that mecA also provides broad selective advantage across diverse chemical environments in the presence of subinhibitory β-lactam concentrations, by protecting the bacteria against increased cell-envelope permeability.

    • Olga Snitser
    • , Dor Russ
    •  & Roy Kishony
  • Article
    | Open Access

    Removal of integrated HIV DNA remains a roadblock for HIV cure. Here, Mancuso et al. show that intravenous administration of an adeno-associated virus-based CRISPR/Cas9 gene editing construct to SIV-infected macaques results in excision of integrated proviral DNA from infected blood cells and tissues known to be viral reservoirs.

    • Pietro Mancuso
    • , Chen Chen
    •  & Kamel Khalili
  • Article
    | Open Access

    The development of specific anti-cytokine/chemokine therapeutic strategies for atherosclerotic disease is challenging. Here, the authors have designed a peptide-based ectodomain mimic of the chemokine receptor CXCR4 that selectively targets MIF but not CXCL12 and blocks experimental atherosclerosis in vivo.

    • Christos Kontos
    • , Omar El Bounkari
    •  & Jürgen Bernhagen
  • Article
    | Open Access

    The analysis of biomolecular frustration yielded insights into several aspects of protein behavior. Here the authors describe a framework to efficiently quantify and localize biomolecular frustration within proteins at atomic resolution, and observe that drug specificity is correlated with a minimally frustrated binding pocket leading to a funneled binding landscape.

    • Mingchen Chen
    • , Xun Chen
    •  & Peter G. Wolynes
  • Article
    | Open Access

    The SARS-CoV-2 main protease (Mpro) is one of two cysteine proteases essential for viral replication. Here, the authors determine the crystal structure of an Mpro acyl intermediate with its native C-terminal autocleavage sequence and the structure of a product bound active site mutant (C145A), which are of interest for antiviral drug development.

    • Jaeyong Lee
    • , Liam J. Worrall
    •  & Natalie C. J. Strynadka
  • Article
    | Open Access

    Nonalcoholic steatohepatitis (NASH) and associated liver fibrosis have limited therapy options. Here the authors report a novel adiponectin-based dual agonist for adiponectin receptors 1 and 2 with a longer half-life, and show that it ameliorates NASH and liver fibrosis in mouse models.

    • Hongjiao Xu
    • , Qian Zhao
    •  & Xianxing Jiang
  • Article
    | Open Access

    Previous work suggests that mitophagy in neurons is could be therapeutic in Alzheimer’s disease (AD). Here, the authors screen a library of drugs and identify UMI-77, a mitophagy inducer with beneficial effects in an AD mouse model, by binding MCL-1, which they identify as a mitophagy receptor.

    • Xufeng Cen
    • , Yanying Chen
    •  & Hongguang Xia
  • Article
    | Open Access

    Antibody-drug conjugates targeting high expression receptors can suffer from poor tumour penetration. Here, the authors use unconjugated antibody to improve the penetration of an antibody-dye conjugate in a clinical study, supporting further clinical investigation of the co-administration strategy.

    • Guolan Lu
    • , Naoki Nishio
    •  & Eben L. Rosenthal
  • Article
    | Open Access

    In this study, the authors combine an anti-viral drug and immune system inducer to treat influenza A and B viral infections in vitro and in vivo. They show that the compound outperforms zanamivir alone as it is still able to clear infection three days post infection, and it can be administered via different routes without reduced efficacy.

    • Xin Liu
    • , Boning Zhang
    •  & Philip S. Low
  • Article
    | Open Access

    The exclusion of T cells from solid tumours is a potentially important mechanism that regulates whether or not cancer patients respond well to checkpoint blocking immunotherapies. Here the authors identify immune phenotypes and mediators of T cell exclusion among ovarian cancer patient samples from the ICON7 phase III trial.

    • Mélanie Desbois
    • , Akshata R. Udyavar
    •  & Yulei Wang