Drug discovery

  • Article | | open

    Here, the authors explore the relationship between socioeconomic position (SEP) across the life course and inflammation in a multi-cohort study and show that educational attainment is most strongly related to inflammation, suggesting that socioeconomic disadvantage in young adulthood is independently associated with later life inflammation.

    • Eloïse Berger
    • , Raphaële Castagné
    • , Marc Chadeau-Hyam
    • , Murielle Bochud
    • , Angelo d’Errico
    • , Martina Gandini
    • , Maryam Karimi
    • , Mika Kivimäki
    • , Vittorio Krogh
    • , Michael Marmot
    • , Salvatore Panico
    • , Martin Preisig
    • , Fulvio Ricceri
    • , Carlotta Sacerdote
    • , Andrew Steptoe
    • , Silvia Stringhini
    • , Rosario Tumino
    • , Paolo Vineis
    • , Cyrille Delpierre
    •  & Michelle Kelly-Irving
  • Article | | open

    Investigation of a reaction scope usually starts with the optimization for a model substrate. Here, the authors apply a time-efficient multi-substrate screening approach to identify a general organocatalyst for the Diels–Alder reaction of cyclopentadiene with α,β-unsaturated aldehydes.

    • Hyejin Kim
    • , Gabriela Gerosa
    • , Jonas Aronow
    • , Pinar Kasaplar
    • , Jie Ouyang
    • , Julia B. Lingnau
    • , Paul Guerry
    • , Christophe Farès
    •  & Benjamin List
  • Article | | open

    Adenovirus based (AdV) vectors are promising platforms for therapeutics and vaccines, but receptor usage of serotypes in clinical development remains unclear. Here, based on crystal structures and modeling, Baker et al. show that HAdV-D26/48 fiber knob protein interacts weakly with CAR but not with CD46 or DSG2.

    • Alexander T. Baker
    • , Alexander Greenshields-Watson
    • , Lynda Coughlan
    • , James A. Davies
    • , Hanni Uusi-Kerttula
    • , David K. Cole
    • , Pierre J. Rizkallah
    •  & Alan L. Parker
  • Article | | open

    Quaternary contacts mediated by an extended heavy-chain framework region 3 (FR3) have been shown to improve binding to HIV envelope and virus neutralization for a few antibodies. Here, Liu et al. engraft such an FR3 loop onto several potent broadly neutralizing antibodies, resulting in improved neutralization activity and pharmacokinetics.

    • Qingbo Liu
    • , Yen-Ting Lai
    • , Peng Zhang
    • , Mark K. Louder
    • , Amarendra Pegu
    • , Reda Rawi
    • , Mangaiarkarasi Asokan
    • , Xuejun Chen
    • , Chen-Hsiang Shen
    • , Gwo-Yu Chuang
    • , Eun Sung Yang
    • , Huiyi Miao
    • , Yuge Wang
    • , Anthony S. Fauci
    • , Peter D. Kwong
    • , John R. Mascola
    •  & Paolo Lusso
  • Article | | open

    Class F receptors are therapeutic targets in human disease and understanding their structural changes during receptor activation may provide important pharmacological insight. Here, the authors combine computational and experimental methods to identify a molecular switch in TM6/7 of Class F receptors that mediates receptor activation.

    • Shane C. Wright
    • , Paweł Kozielewicz
    • , Maria Kowalski-Jahn
    • , Julian Petersen
    • , Carl-Fredrik Bowin
    • , Greg Slodkowicz
    • , Maria Marti-Solano
    • , David Rodríguez
    • , Belma Hot
    • , Najeah Okashah
    • , Katerina Strakova
    • , Jana Valnohova
    • , M. Madan Babu
    • , Nevin A. Lambert
    • , Jens Carlsson
    •  & Gunnar Schulte
  • Article | | open

    Diverse interactions between the nervous and immune systems have been shown, but specific mechanistic insights are still lacking. Here the authors show, using both mouse inflammation models and clinical correlation, that adrenergic nerve may ameliorate inflammation by inducing repulsive guidance molecule A signalling.

    • Andreas Körner
    • , Martin Schlegel
    • , Torsten Kaussen
    • , Verena Gudernatsch
    • , Georg Hansmann
    • , Timo Schumacher
    • , Martin Giera
    •  & Valbona Mirakaj
  • Article | | open

    Thermally activated delayed fluorescence is a mechanism for enhancing the efficiency of organic light emitting diodes by harvesting triplet excitons, but there is still a need to design more efficient materials. Here, the authors rationally design and characterize a series of π-extended boron- and nitrogen-doped nanographenes as promising candidates.

    • Anton Pershin
    • , David Hall
    • , Vincent Lemaur
    • , Juan-Carlos Sancho-Garcia
    • , Luca Muccioli
    • , Eli Zysman-Colman
    • , David Beljonne
    •  & Yoann Olivier
  • Article | | open

    Mother Nature is a valuable resource for the discovery of drug and agricultural chemicals. Here, the authors show that 7-deoxy-sedoheptulose produced by a cyanobacterium is an antimicrobial and herbicidal compound that acts through inhibition of 3-dehydroquniate synthase in the shikimate pathway.

    • Klaus Brilisauer
    • , Johanna Rapp
    • , Pascal Rath
    • , Anna Schöllhorn
    • , Lisa Bleul
    • , Elisabeth Weiß
    • , Mark Stahl
    • , Stephanie Grond
    •  & Karl Forchhammer
  • Article | | open

    Synthetic chemists develop a "chemical intuition" over years of experience in the lab. Here the authors combine machine learning of (partially) failed experiments with robotic synthesis to capture this intuition used in searching for the optimal synthesis conditions of metal-organic frameworks.

    • Seyed Mohamad Moosavi
    • , Arunraj Chidambaram
    • , Leopold Talirz
    • , Maciej Haranczyk
    • , Kyriakos C. Stylianou
    •  & Berend Smit
  • Article | | open

    Combination therapy for Buruli ulcer (BU) is suboptimal. Here, Liu et al. show that the candidate drug TB47 has potent bactericidal activity against Mycobacterium ulcerans in vitro and in a mouse model, which underscores its potential for shortening the course of BU and treating other mycobacterial diseases.

    • Yang Liu
    • , Yamin Gao
    • , Jianxiong Liu
    • , Yaoju Tan
    • , Zhiyong Liu
    • , Chiranjibi Chhotaray
    • , Huofeng Jiang
    • , Zhili Lu
    • , Gift Chiwala
    • , Shuai Wang
    • , Gaelle Makafe
    • , Md Mahmudul Islam
    • , H. M. Adnan Hameed
    • , Xingshan Cai
    • , Changwei Wang
    • , Xinjie Li
    • , Shouyong Tan
    •  & Tianyu Zhang
  • Article | | open

    Adeno-associated viral vectors (AAV) are being developed for gene therapy of skeletal muscle, but it is a challenge to achieve robust gene expression. Here, the authors identify muscle-specific cisregulatory elements that lead to a substantial increase in micro-dystrophin and follistatin expression, resulting in a safe and sustainable rescue of the dystrophic phenotype in mouse models.

    • S. Sarcar
    • , W. Tulalamba
    • , M. Y. Rincon
    • , J. Tipanee
    • , H. Q. Pham
    • , H. Evens
    • , D. Boon
    • , E. Samara-Kuko
    • , M. Keyaerts
    • , M. Loperfido
    • , E. Berardi
    • , S. Jarmin
    • , P. In’t Veld
    • , G. Dickson
    • , T. Lahoutte
    • , M. Sampaolesi
    • , P. De Bleser
    • , T. VandenDriessche
    •  & M. K. Chuah
  • Article | | open

    The delivery of single therapeutic microRNAs in brain cancers is challenging. Here, the authors engineer three neuronal microRNAs (miR-124, 128 and 137) into a cluster that, targeting oncogenic chromatin repressors, increases survival of GBM-bearing mice when combined with chemotherapy.

    • Vivek Bhaskaran
    • , Michal O. Nowicki
    • , Mahmoud Idriss
    • , Miguel A. Jimenez
    • , Gianmarco Lugli
    • , Josie L. Hayes
    • , Ahmad Bakur Mahmoud
    • , Rachel E. Zane
    • , Carmela Passaro
    • , Keith L. Ligon
    • , Daphne Haas-Kogan
    • , Agnieszka Bronisz
    • , Jakub Godlewski
    • , Sean E. Lawler
    • , E. Antonio Chiocca
    •  & Pierpaolo Peruzzi
  • Article | | open

    While the conversion of greenhouse CO2 to chemical fuels offers a promising renewable energy technology, there is a dire need for new materials. Here, authors report the largest CO2 photocathode search using a first-principles approach to identify both known and unreported candidate photocatalysts.

    • Arunima K. Singh
    • , Joseph H. Montoya
    • , John M. Gregoire
    •  & Kristin A. Persson
  • Article | | open

    The incomplete nature and undefined structure of the existing catalysis research data has prevented comprehensive knowledge extraction. Here, the authors report a novel meta-analysis method that identifies correlations between a catalyst’s physico-chemical properties and its performance in a particular reaction.

    • Roman Schmack
    • , Alexandra Friedrich
    • , Evgenii V. Kondratenko
    • , Jörg Polte
    • , Axel Werwatz
    •  & Ralph Kraehnert
  • Article | | open

    The chaperone Hsp90 is a potential target for the development of drugs against fungal pathogens. Here the authors determine the structure of the Hsp90 nucleotide-binding domain from Candida albicans, which they use to design an inhibitor and demonstrate its selectivity for the fungal enzyme, both biochemically and in cells.

    • Luke Whitesell
    • , Nicole Robbins
    • , David S. Huang
    • , Catherine A. McLellan
    • , Tanvi Shekhar-Guturja
    • , Emmanuelle V. LeBlanc
    • , Catherine S. Nation
    • , Raymond Hui
    • , Ashley Hutchinson
    • , Cathy Collins
    • , Sharanya Chatterjee
    • , Richard Trilles
    • , Jinglin L. Xie
    • , Damian J. Krysan
    • , Susan Lindquist
    • , John A. Porco Jr.
    • , Utpal Tatu
    • , Lauren E. Brown
    • , Juan Pizarro
    •  & Leah E. Cowen
  • Article | | open

    ER stress and UPR are implicated in various cancers. Here, the authors show that one of the canonical UPR pathways, IRE1α-XBP1 regulates c-MYC signaling to promote prostate tumorigenesis, and pharmacological inhibition of IRE1α with MKC8866 inhibits prostate cancer growth and synergizes with clinically used prostate cancer drugs.

    • Xia Sheng
    • , Hatice Zeynep Nenseth
    • , Su Qu
    • , Omer F. Kuzu
    • , Turid Frahnow
    • , Lukas Simon
    • , Stephanie Greene
    • , Qingping Zeng
    • , Ladan Fazli
    • , Paul S. Rennie
    • , Ian G. Mills
    • , Håvard Danielsen
    • , Fabian Theis
    • , John B. Patterson
    • , Yang Jin
    •  & Fahri Saatcioglu
  • Article | | open

    Real-time deformability cytometry (RT-DC) is used for mechanical cell phenotyping but is limited to a single snapshot per cell and can only measure elastic modulus. Here the authors introduce dynamic RT-DC which can measure elasticity and viscosity in single cells by following dynamic cell shape changes.

    • Bob Fregin
    • , Fabian Czerwinski
    • , Doreen Biedenweg
    • , Salvatore Girardo
    • , Stefan Gross
    • , Konstanze Aurich
    •  & Oliver Otto
  • Article | | open

    Enhanced Wnt receptor activity is a major cause of cancer development. Here the authors identify camelid single-domain antibody fragments (VHHs) that bind to the Wnt receptor LRP5/6 ectodomain, determine the crystal structures and show that these VHHs selectively inhibit Wnt3- mediated cellular responses and block the growth of mutant Wnt-hypersensitive intestinal tumor organoids.

    • Nicola Fenderico
    • , Revina C. van Scherpenzeel
    • , Michael Goldflam
    • , Davide Proverbio
    • , Ingrid Jordens
    • , Tomica Kralj
    • , Sarah Stryeck
    • , Tarek Z. Bass
    • , Guy Hermans
    • , Christopher Ullman
    • , Teodor Aastrup
    • , Piet Gros
    •  & Madelon M. Maurice
  • Article | | open

    Tolerance and other side effects are important limitations to the use of opioids as analgesics. In this study, the authors generated mice lacking phosphorylation sites on the µ-opioid receptor to assess their contribution to the analgesic, tolerance and side effect profile of opioid analgesics.

    • A. Kliewer
    • , F. Schmiedel
    • , S. Sianati
    • , A. Bailey
    • , J. T. Bateman
    • , E. S. Levitt
    • , J. T. Williams
    • , M. J. Christie
    •  & S. Schulz
  • Article | | open

    Osteoarthritis (OA) is associated with cartilage degeneration, and no effective therapy exists. Here, the authors show that the HPIP protein modulates OA progression by regulating Wnt signaling, and that its knockdown in joints via AAV-mediated gene silencing attentuates pathology.

    • Quanbo Ji
    • , Xiaojie Xu
    • , Lei Kang
    • , Yameng Xu
    • , Jingbo Xiao
    • , Stuart B. Goodman
    • , Xiang Zhu
    • , Wenchao Li
    • , Juan Liu
    • , Xu Gao
    • , Zhifeng Yan
    • , Yuxuan Zheng
    • , Zheng Wang
    • , William J. Maloney
    • , Qinong Ye
    •  & Yan Wang
  • Article | | open

    Genetic screens are important tools to identify host factors associated with viral infections. Here, Flint et al. perform a genome-wide CRISPR screen using infectious Ebola virus (EBOV) and show that the host transferase GNPTAB is required for EBOV infection and a potential target for antiviral therapies

    • Mike Flint
    • , Payel Chatterjee
    • , David L. Lin
    • , Laura K. McMullan
    • , Punya Shrivastava-Ranjan
    • , Éric Bergeron
    • , Michael K. Lo
    • , Stephen R. Welch
    • , Stuart T. Nichol
    • , Andrew W. Tai
    •  & Christina F. Spiropoulou
  • Article | | open

    Preparation of xanthene-containing compounds has been limited due to structural bias existing methods pose. Here, the authors developed a mild, diversity-oriented method for rhodamines synthesis, leading to the finding of compounds with antibacterial potency against a variety of bacterial species.

    • Xiao Luo
    • , Liujia Qian
    • , Yansheng Xiao
    • , Yao Tang
    • , Yang Zhao
    • , Xia Wang
    • , Luyan Gu
    • , Zuhai Lei
    • , Jianming Bao
    • , Jiahui Wu
    • , Tingting He
    • , Fupin Hu
    • , Jing Zheng
    • , Honglin Li
    • , Weiping Zhu
    • , Lei Shao
    • , Xiaojing Dong
    • , Daijie Chen
    • , Xuhong Qian
    •  & Youjun Yang
  • Article | | open

    FLT3 is commonly mutated in acute myeloid leukaemia and treatment with FLT3 inhibitors often ends with relapse. Here, the authors perform exome sequencing of samples from patients treated with the FLT3 inhibitor, crenolanib, to show that resistance occurs due to diverse molecular mechanisms, not primarily due to secondary FLT3 mutations.

    • Haijiao Zhang
    • , Samantha Savage
    • , Anna Reister Schultz
    • , Daniel Bottomly
    • , Libbey White
    • , Erik Segerdell
    • , Beth Wilmot
    • , Shannon K. McWeeney
    • , Christopher A. Eide
    • , Tamilla Nechiporuk
    • , Amy Carlos
    • , Rachel Henson
    • , Chenwei Lin
    • , Robert Searles
    • , Hoang Ho
    • , Yee Ling Lam
    • , Richard Sweat
    • , Courtney Follit
    • , Vinay Jain
    • , Evan Lind
    • , Gautam Borthakur
    • , Guillermo Garcia-Manero
    • , Farhad Ravandi
    • , Hagop M. Kantarjian
    • , Jorge Cortes
    • , Robert Collins
    • , Daelynn R. Buelow
    • , Sharyn D. Baker
    • , Brian J. Druker
    •  & Jeffrey W. Tyner
  • Article | | open

    Salmonella Typhimurium replicates within host phagocytes. Here, the authors show that a known psychoactive drug (metergoline) inhibits growth of the pathogen in macrophages, disrupts the proton motive force at the bacterial cytoplasmic membrane, and extends animal survival during systemic infection.

    • Michael J. Ellis
    • , Caressa N. Tsai
    • , Jarrod W. Johnson
    • , Shawn French
    • , Wael Elhenawy
    • , Steffen Porwollik
    • , Helene Andrews-Polymenis
    • , Michael McClelland
    • , Jakob Magolan
    • , Brian K. Coombes
    •  & Eric D. Brown
  • Article | | open

    Small molecule modulators of RNA splicing have therapeutic potential in tumours bearing spliceosome mutations. Here, the authors identify BCL2 genes have differential sensitivities to SF3b-targeting splicing modulators and combination of SF3b-targeting splicing modulators and BCLxL inhibition induces synergistic cytotoxicity in cancer cells.

    • Daniel Aird
    • , Teng Teng
    • , Chia-Ling Huang
    • , Ermira Pazolli
    • , Deepti Banka
    • , Kahlin Cheung-Ong
    • , Cheryl Eifert
    • , Craig Furman
    • , Zhenhua Jeremy Wu
    • , Michael Seiler
    • , Silvia Buonamici
    • , Peter Fekkes
    • , Craig Karr
    • , James Palacino
    • , Eunice Park
    • , Peter G. Smith
    • , Lihua Yu
    • , Yoshiharu Mizui
    • , Markus Warmuth
    • , Agustin Chicas
    • , Laura Corson
    •  & Ping Zhu
  • Article | | open

    Viruses rely on host cell metabolism for replication, making these pathways potential therapeutic targets. Here, the authors show that AM580, a retinoid derivative and RAR-α agonist, affects replication of several RNA viruses by interfering with the activity of SREBP.

    • Shuofeng Yuan
    • , Hin Chu
    • , Jasper Fuk-Woo Chan
    • , Zi-Wei Ye
    • , Lei Wen
    • , Bingpeng Yan
    • , Pok-Man Lai
    • , Kah-Meng Tee
    • , Jingjing Huang
    • , Dongdong Chen
    • , Cun Li
    • , Xiaoyu Zhao
    • , Dong Yang
    • , Man Chun Chiu
    • , Cyril Yip
    • , Vincent Kwok-Man Poon
    • , Chris Chung-Sing Chan
    • , Kong-Hung Sze
    • , Jie Zhou
    • , Ivy Hau-Yee Chan
    • , Kin-Hang Kok
    • , Kelvin Kai-Wang To
    • , Richard Yi-Tsun Kao
    • , Johnson Yiu-Nam Lau
    • , Dong-Yan Jin
    • , Stanley Perlman
    •  & Kwok-Yung Yuen
  • Article | | open

    Multiple organ dysfunction syndrome (MODS) is a serious event that can occur following infection or tissue injury, and is partly mediated by histones released in circulation. Here, the authors develop aptamers that neutralise histones involved in MODS, and demonstrate efficacy in human cells and in mouse models.

    • Kevin T. Urak
    • , Giselle N. Blanco
    • , Shambhavi Shubham
    • , Li-Hsien Lin
    • , Justin P. Dassie
    • , William H. Thiel
    • , Yani Chen
    • , Vijay Kumar Sonkar
    • , Beilei Lei
    • , Shubha Murthy
    • , Wade R. Gutierrez
    • , Mary E. Wilson
    • , Jonathan A. Stiber
    • , Julia Klesney-Tait
    • , Sanjana Dayal
    • , Francis J. Miller Jr
    •  & Paloma H. Giangrande
  • Article | | open

    Squalene epoxidase (SQLE) is a key enzyme in cholesterol biosynthesis and is a target for hypercholesteremia and cancer drug development. Here the authors present the crystal structures of the human SQLE catalytic domain alone and bound with small molecule inhibitors, which will facilitate the development of next-generation SQLE inhibitors.

    • Anil K. Padyana
    • , Stefan Gross
    • , Lei Jin
    • , Giovanni Cianchetta
    • , Rohini Narayanaswamy
    • , Feng Wang
    • , Rui Wang
    • , Cheng Fang
    • , Xiaobing Lv
    • , Scott A. Biller
    • , Lenny Dang
    • , Christopher E. Mahoney
    • , Nelamangala Nagaraja
    • , David Pirman
    • , Zhihua Sui
    • , Janeta Popovici-Muller
    •  & Gromoslaw A. Smolen
  • Article | | open

    The oncogene STAT5 is involved in cancer cell proliferation. Here, the authors use STAT5 protein to assemble its own small molecule inhibitors via Mannich ligation (three-component-reactions) and show that the resultant ligands can inhibit the proliferation of cancer cells in a mouse model.

    • Ee Lin Wong
    • , Eric Nawrotzky
    • , Christoph Arkona
    • , Boo Geun Kim
    • , Samuel Beligny
    • , Xinning Wang
    • , Stefan Wagner
    • , Michael Lisurek
    • , Dirk Carstanjen
    •  & Jörg Rademann
  • Article | | open

    Halogen bonding can be exploited for the design of functional supramolecular materials, but heavier elements that are known to accept a halogen bond remain limited. Here, the authors demonstrate the formation of two-component cocrystals based on halogen bonds with phosphorus, arsenic and antimony.

    • Katarina Lisac
    • , Filip Topić
    • , Mihails Arhangelskis
    • , Sara Cepić
    • , Patrick A. Julien
    • , Christopher W. Nickels
    • , Andrew J. Morris
    • , Tomislav Friščić
    •  & Dominik Cinčić
  • Article | | open

    Temsavir, a compound that inhibits HIV entry by binding envelope (Env), is currently in clinical development. Here, Lai et al. identify a more than 10-fold improved compound and, using lattice engineering, obtain crystal structures that give insights into improved inhibition between small molecules and Env.

    • Yen-Ting Lai
    • , Tao Wang
    • , Sijy O’Dell
    • , Mark K. Louder
    • , Arne Schön
    • , Crystal S. F. Cheung
    • , Gwo-Yu Chuang
    • , Aliaksandr Druz
    • , Bob Lin
    • , Krisha McKee
    • , Dongjun Peng
    • , Yongping Yang
    • , Baoshan Zhang
    • , Alon Herschhorn
    • , Joseph Sodroski
    • , Robert T. Bailer
    • , Nicole A. Doria-Rose
    • , John R. Mascola
    • , David R. Langley
    •  & Peter D. Kwong
  • Article | | open

    CO2 conversion to reduced products provides a use for greenhouse gases, but reaction complexity stymies mechanistic studies. Here, authors present a microkinetic model for CO2 and CO reduction on copper, based on ab initio simulations, to elucidate pH’s impact on competitive reaction pathways.

    • Xinyan Liu
    • , Philomena Schlexer
    • , Jianping Xiao
    • , Yongfei Ji
    • , Lei Wang
    • , Robert B. Sandberg
    • , Michael Tang
    • , Kristopher S. Brown
    • , Hongjie Peng
    • , Stefan Ringe
    • , Christopher Hahn
    • , Thomas F. Jaramillo
    • , Jens K. Nørskov
    •  & Karen Chan
  • Article | | open

    Parasitic nematodes causing onchocerciasis and lymphatic filariasis rely on a bacterial endosymbiont, Wolbachia, which is a validated therapeutic target. Here, Clare et al. perform a high-throughput screen of 1.3 million compounds and identify 5 chemotypes with faster kill rates than existing anti-Wolbachia drugs.

    • Rachel H. Clare
    • , Catherine Bardelle
    • , Paul Harper
    • , W. David Hong
    • , Ulf Börjesson
    • , Kelly L. Johnston
    • , Matthew Collier
    • , Laura Myhill
    • , Andrew Cassidy
    • , Darren Plant
    • , Helen Plant
    • , Roger Clark
    • , Darren A. N. Cook
    • , Andrew Steven
    • , John Archer
    • , Paul McGillan
    • , Sitthivut Charoensutthivarakul
    • , Jaclyn Bibby
    • , Raman Sharma
    • , Gemma L. Nixon
    • , Barton E. Slatko
    • , Lindsey Cantin
    • , Bo Wu
    • , Joseph Turner
    • , Louise Ford
    • , Kirsty Rich
    • , Mark Wigglesworth
    • , Neil G. Berry
    • , Paul M. O’Neill
    • , Mark J. Taylor
    •  & Stephen A. Ward
  • Article | | open

    High expression of Mcl-1 promotes tumorigenesis and resistance to anticancer therapies. Here they report a macrocyclic molecule with high selectivity and affinity for Mcl-1 that exhibits potent anti-tumor effects as single agent and in combination with bortezomib or venetoclax in preclinical models of multiple myeloma and acute myeloid leukemia.

    • Adriana E. Tron
    • , Matthew A. Belmonte
    • , Ammar Adam
    • , Brian M. Aquila
    • , Lawrence H. Boise
    • , Elisabetta Chiarparin
    • , Justin Cidado
    • , Kevin J. Embrey
    • , Eric Gangl
    • , Francis D. Gibbons
    • , Gareth P. Gregory
    • , David Hargreaves
    • , J. Adam Hendricks
    • , Jeffrey W. Johannes
    • , Ricky W. Johnstone
    • , Steven L. Kazmirski
    • , Jason G. Kettle
    • , Michelle L. Lamb
    • , Shannon M. Matulis
    • , Ajay K. Nooka
    • , Martin J. Packer
    • , Bo Peng
    • , Philip B. Rawlins
    • , Daniel W. Robbins
    • , Alwin G. Schuller
    • , Nancy Su
    • , Wenzhan Yang
    • , Qing Ye
    • , Xiaolan Zheng
    • , J. Paul Secrist
    • , Edwin A. Clark
    • , David M. Wilson
    • , Stephen E. Fawell
    •  & Alexander W. Hird
  • Article | | open

    In gene regulation, diversification at the transcriptome 3′end is linked to differentiation and dedifferentiation. Here, the authors discover extensive transcriptome 3′end-alterations in neuroblastoma, regulated by PCF11, and provide an interactive data repository of transcriptome-wide alternative polyadenylation.

    • Anton Ogorodnikov
    • , Michal Levin
    • , Surendra Tattikota
    • , Sergey Tokalov
    • , Mainul Hoque
    • , Denise Scherzinger
    • , Federico Marini
    • , Ansgar Poetsch
    • , Harald Binder
    • , Stephan Macher-Göppinger
    • , Hans Christian Probst
    • , Bin Tian
    • , Michael Schaefer
    • , Karl J. Lackner
    • , Frank Westermann
    •  & Sven Danckwardt
  • Article | | open

    While nanocarrier-based drug delivery is a promising therapeutic approach, in situ characterization of drug nanocarriers in blood remains difficult. Here, the authors demonstrate how the fluorescence correlation spectroscopy can be used to directly characterize drug nanocarriers in flowing blood.

    • Inka Negwer
    • , Andreas Best
    • , Meike Schinnerer
    • , Olga Schäfer
    • , Leon Capeloa
    • , Manfred Wagner
    • , Manfred Schmidt
    • , Volker Mailänder
    • , Mark Helm
    • , Matthias Barz
    • , Hans-Jürgen Butt
    •  & Kaloian Koynov
  • Article | | open

    Activation of PI3K plays a role in pulmonary inflammation. Here, the authors develop a drug inhibitor of PI3K, and show that it inhibits lung inflammation and damage in mouse models of asthma and lung fibrosis.

    • Carlo C. Campa
    • , Rangel L. Silva
    • , Jean P. Margaria
    • , Tracey Pirali
    • , Matheus S. Mattos
    • , Lucas R. Kraemer
    • , Diego C. Reis
    • , Giorgio Grosa
    • , Francesca Copperi
    • , Eduardo M. Dalmarco
    • , Roberto C. P. Lima-Júnior
    • , Silvio Aprile
    • , Valentina Sala
    • , Federica Dal Bello
    • , Douglas Silva Prado
    • , Jose Carlos Alves-Filho
    • , Claudio Medana
    • , Geovanni D. Cassali
    • , Gian Cesare Tron
    • , Mauro M. Teixeira
    • , Elisa Ciraolo
    • , Remo C. Russo
    •  & Emilio Hirsch
  • Article | | open

    Late diagnosis and ineffective treatment of fungal infections lead to high mortality. Here, Rudkin et al. generate anti-Candida human monoclonal antibodies with diagnostic and therapeutic potential, by expressing recombinant antibodies from genes cloned from B cells of patients suffering candidiasis.

    • Fiona M. Rudkin
    • , Ingrida Raziunaite
    • , Hillary Workman
    • , Sosthene Essono
    • , Rodrigo Belmonte
    • , Donna M. MacCallum
    • , Elizabeth M. Johnson
    • , Lisete M. Silva
    • , Angelina S. Palma
    • , Ten Feizi
    • , Allan Jensen
    • , Lars P. Erwig
    •  & Neil A. R. Gow
  • Article | | open

    The molecular pathway(s) driving antipsychotics (AP) induced hyperphagia remains unclear. A novel C. elegans system is used here to screen for FDA approved drugs that selectively suppresses this response, unraveling potential molecular mediators influencing AP induced hyperphagia in mouse models.

    • Anabel Perez-Gomez
    • , Maria Carretero
    • , Natalie Weber
    • , Veronika Peterka
    • , Alan To
    • , Viktoriya Titova
    • , Gregory Solis
    • , Olivia Osborn
    •  & Michael Petrascheck
  • Article | | open

    Sodium-dependent glucose transporters (SGLTs) transport sugars across the plasma membrane and play important roles in renal sugar reabsorption. Here authors develop structural models of human SGLT1/2 (hSGLT1/2) in complex with inhibitors which helps to understand inhibitor subtype selectivity.

    • Paola Bisignano
    • , Chiara Ghezzi
    • , Hyunil Jo
    • , Nicholas F. Polizzi
    • , Thorsten Althoff
    • , Chakrapani Kalyanaraman
    • , Rosmarie Friemann
    • , Matthew P. Jacobson
    • , Ernest M. Wright
    •  & Michael Grabe
  • Article | | open

    Clostridium difficile causes diarrhea and colitis by producing up to three different protein toxins. Here, Tam et al. show that an anthelmintic drug, niclosamide, inhibits the pathogenesis of all three toxins by targeting a host process required for toxin entry into host cells, without disrupting the gut microbiota.

    • John Tam
    • , Therwa Hamza
    • , Bing Ma
    • , Kevin Chen
    • , Greg L. Beilhartz
    • , Jacques Ravel
    • , Hanping Feng
    •  & Roman A. Melnyk
  • Article | | open

    The tuberculosis pandemic requires new methods for diagnosing and containing infections prior to active disease. Here, the authors performed a multi-site observational study within sub-Saharan Africa and present serum and plasma metabolic signatures that can predict the onset of active TB with a high degree of sensitivity and specificity.

    • January Weiner 3rd
    • , Jeroen Maertzdorf
    • , Jayne S. Sutherland
    • , Fergal J. Duffy
    • , Ethan Thompson
    • , Sara Suliman
    • , Gayle McEwen
    • , Bonnie Thiel
    • , Shreemanta K. Parida
    • , Joanna Zyla
    • , Willem A. Hanekom
    • , Robert P. Mohney
    • , W. Henry Boom
    • , Harriet Mayanja-Kizza
    • , Rawleigh Howe
    • , Hazel M. Dockrell
    • , Tom H. M. Ottenhoff
    • , Thomas J. Scriba
    • , Daniel E. Zak
    • , Gerhard Walzl
    • , Stefan H. E. Kaufmann
    • , Almaz Abebe
    • , Brian Abel
    • , Richard Adegbola
    • , Ifedayo Adetifa
    • , Lyn Ambrose
    • , Peter Andersen
    • , Martin Antonio
    • , Abraham Aseffa
    • , Debbie van Baarle
    • , Lew Barker
    • , Yonas Bekele
    • , Nicole Bilek
    • , Gillian F. Black
    • , Mark Bowmaker
    • , Keith Branson
    • , Michael Brennan
    • , Novel N. Chegou
    • , Femia Chilongo
    • , William Kwong Chung
    • , Tumani Corrah
    • , Ameilia C. Crampin
    • , Mark Doherty
    • , Gregory Dolganov
    • , Simon Donkor
    • , Katrina Downing
    • , Michelle Fisher
    • , Kees L. M. C. Franken
    • , Neil French
    • , Larry Geiter
    • , Annemieke Geluk
    • , Robert Golinski
    • , Patricia Gorak-Stolinska
    • , Marielle C. Haks
    • , Philip Hill
    • , Jane Hughes
    • , Yun-Gyoung Hur
    • , Rachel Iwnetu
    • , Marc Jacobson
    • , Moses Joloba
    • , Simone A. Joosten
    • , Benjamin Kagina
    • , Desta Kassa
    • , Hussein Kisingo
    • , Michel R. Klein
    • , Magdalena Kriel
    • , Maeve Lalor
    • , Ji-Sook Lee
    • , Andre G. Loxton
    • , Hassan Mahomed
    • , Krista E. van Meijgaarden
    • , Tsehayenesh Mesele
    • , Frank Miedema
    • , Adane Mihret
    • , Humphrey Mulenga
    • , Stefanie Muller
    • , Hazzie Mvula
    • , Nonhlanhla Nene
    • , Bagrey Ngwira
    • , Mary Nsereko
    • , Brenda Okwera
    • , Martin Ota
    • , Adam Penn-Nicholson
    • , Nelita Du Plessis
    • , S. Ramachandran
    • , Ida Rosenkrands
    • , Jerry Sadoff
    • , Jacky Saul
    • , Gary Schoolnik
    • , Felanji Simukonda
    • , Donata Sizemore
    • , Steven Smith
    • , Anne Ben Smith
    • , Gian van der Spuy
    • , Kim Stanley
    • , David Tabb
    • , Mesfin Tafesse
    • , Belete Tegbaru
    • , Toyin Togun
    • , Gerhardus Tromp
    • , Tran Van
    • , Kate Watkins
    • , Frank Weichold
    • , Karin Weldingh
    • , Lawrence Yamuah
    •  & Sarah Zalwango
  • Article | | open

    Direct targeting of mutant KRas is challenging and alternative approaches are needed. Here they show glycogen synthase kinase 3 (GSK3) to be required for the growth and survival of human mutant KRas-dependent tumors but dispensable for mutant KRas-independent tumors and show GSK3 inhibition to inhibit in vivo growth of Kras mutant patient-derived pancreatic tumors.

    • Aslamuzzaman Kazi
    • , Shengyan Xiang
    • , Hua Yang
    • , Daniel Delitto
    • , José Trevino
    • , Rays H. Y. Jiang
    • , Muhammad Ayaz
    • , Harshani R. Lawrence
    • , Perry Kennedy
    •  & Saïd M. Sebti
  • Article | | open

    DNA methylation is an epigenetic modification that control genetic programs. Here, the authors found that the methylation landscape influences the physicochemical properties of DNA and that it can serve as a universal cancer biomarker, and developed a one-step assay for the detection of cancer DNA.

    • Abu Ali Ibn Sina
    • , Laura G. Carrascosa
    • , Ziyu Liang
    • , Yadveer S. Grewal
    • , Andri Wardiana
    • , Muhammad J. A. Shiddiky
    • , Robert A. Gardiner
    • , Hemamali Samaratunga
    • , Maher K. Gandhi
    • , Rodney J. Scott
    • , Darren Korbie
    •  & Matt Trau
  • Article | | open

    The fast and accurate determination of molecular properties is particularly crucial in drug discovery. Here, the authors employ supervised machine learning to treat differential mobility spectrometry – mass spectrometry data for ten classes of drug candidates and predict several condensed-phase properties.

    • Stephen W. C. Walker
    • , Ahdia Anwar
    • , Jarrod M. Psutka
    • , Jeff Crouse
    • , Chang Liu
    • , J. C. Yves Le Blanc
    • , Justin Montgomery
    • , Gilles H. Goetz
    • , John S. Janiszewski
    • , J. Larry Campbell
    •  & W. Scott Hopkins
  • Article | | open

    Antifungal resistance due to upregulation of efflux pumps is common in Candida albicans. Here, the authors show that conjugation with mitochondria-targeting triphenylphosphonium cation can enhance or restore the antifungal activity of potential efflux pump substrates.

    • Wenqiang Chang
    • , Jun Liu
    • , Ming Zhang
    • , Hongzhuo Shi
    • , Sha Zheng
    • , Xueyang Jin
    • , Yanhui Gao
    • , Shuqi Wang
    • , Aiguo Ji
    •  & Hongxiang Lou
  • Article | | open

    The methylation status of circulating cell-free DNA (cfDNA) can be informative about recent cell death events. Here the authors present an approach to determine the tissue origins of cfDNA, using a reference methylation atlas of 25 human tissues and cell types, and find that cfDNA from patients reveals tissue contributions that agree with clinical findings.

    • Joshua Moss
    • , Judith Magenheim
    • , Daniel Neiman
    • , Hai Zemmour
    • , Netanel Loyfer
    • , Amit Korach
    • , Yaacov Samet
    • , Myriam Maoz
    • , Henrik Druid
    • , Peter Arner
    • , Keng-Yeh Fu
    • , Endre Kiss
    • , Kirsty L. Spalding
    • , Giora Landesberg
    • , Aviad Zick
    • , Albert Grinshpun
    • , A. M. James Shapiro
    • , Markus Grompe
    • , Avigail Dreazan Wittenberg
    • , Benjamin Glaser
    • , Ruth Shemer
    • , Tommy Kaplan
    •  & Yuval Dor
  • Article | | open

    Efficient biosynthesis of lactams is still undesirable due to lacking of suitable enzyme. Here, the authors develop a sensitive transcription factor-based biosensor for high-throughput screening of marine metagenome and find a cyclase that can cyclize ω-amino fatty acids to lactam.

    • Soo-Jin Yeom
    • , Moonjeong Kim
    • , Kil Koang Kwon
    • , Yaoyao Fu
    • , Eugene Rha
    • , Sung-Hyun Park
    • , Hyewon Lee
    • , Haseong Kim
    • , Dae-Hee Lee
    • , Dong-Myung Kim
    •  & Seung-Goo Lee
  • Article | | open

    The side effects of cancer drugs limit their utility. Here, the authors developed a method in which an inactive (prodrug) version of the cancer drug doxorubicin enters tumour cells and then gets activated inside the cells upon a trigger facilitated by enzyme-instructed supramolecular self-assembly.

    • Qingxin Yao
    • , Feng Lin
    • , Xinyuan Fan
    • , Yanpu Wang
    • , Ye Liu
    • , Zhaofei Liu
    • , Xingyu Jiang
    • , Peng R. Chen
    •  & Yuan Gao