Drug discovery

  • Article
    | Open Access

    A strategy to control HIV-1 infection is to stably repress HIV-1 and induce “deep latency”. Here the authors show that a recombinant anti-HIV-1-1 protein can be packaged as mRNA into exosomes and delivered systemically to repress HIV-1-1 within the context of virus infected mice and achieve long term silencing of HIV-1-1 expression.

    • Surya Shrivastava
    • , Roslyn M. Ray
    •  & Kevin V. Morris
  • Article
    | Open Access

    Isopropenyl ethers (IPPEs) are essential intermediates for obtaining ketal-based prodrugs and biomaterials, but traditional approaches for their synthesis are limited by poor functional group compatibility and harsh reaction conditions. Here, the authors report an organocatalytic transisopropenylation approach for IPPE synthesis in mild reaction conditions and with wide range of substrates, and use it to prepare acid-sensitive ketal-linked prodrugs and biomaterials.

    • Na Yu
    • , Yang Xu
    •  & Shutao Guo
  • Article
    | Open Access

    Mitochondrial dysfunction is a common hallmark of neurological disorders. Here, the authors identify CHIR99021 as a potent enhancer of mitochondrial function, which improved mitochondrial phenotypes in Huntington’s disease models. CHIR99021 was shown to stabilize calpastatin, which suppressed calpain activation and Drp1-induced mitochondrial fragmentation.

    • Di Hu
    • , Xiaoyan Sun
    •  & Xin Qi
  • Article
    | Open Access

    Elucidating specific effects of protein kinase Akt isoforms remains challenging. Here, the authors establish an Akt isoform-dependent cellular model system and use it, together with X-ray crystallography and structure-based ligand design, to develop isoform-selective covalent-allosteric Akt inhibitors

    • Lena Quambusch
    • , Laura Depta
    •  & Daniel Rauh
  • Article
    | Open Access

    Protein delivery with cell-penetrating peptides suffers from ineffective endosomal escape and low tolerance in serum, thereby limiting treatment success. Here the authors present an intracellular protein delivery system and demonstrate efficient delivery in vitro and therapeutic efficacy in a liver failure model in vivo.

    • Siyuan Yu
    • , Han Yang
    •  & Ningshao Xia
  • Article
    | Open Access

    Vilazodone (VLZ) is a drug for the treatment of major depressive disorders that targets the serotonin transporter (SERT). Here, the authors combine pharmacology measurements and cryo-EM structural analysis to characterize VLZ binding to SERT and observe that VLZ exhibits non-competitive inhibition of serotonin transport and binds with nanomolar affinity to an allosteric site in SERT.

    • Per Plenge
    • , Dongxue Yang
    •  & Claus J. Loland
  • Article
    | Open Access

    Here the authors report the isolation and structural and biological characterization of a humanized angiotensin-converting enzyme 2 (ACE2)-blocking antibody, which exterts potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages both in vitro and in hACE2 mouse model.

    • Yanyun Du
    • , Rui Shi
    •  & Jinghua Yan
  • Article
    | Open Access

    The use of synthetic organisms could provide opportunities for discovery and advanced manufacturing of medical drugs. Here the authors use a semi-synthetic organism with an expanded genetic code to generate site-specific chemical modifications in human IL-2.

    • Jerod L. Ptacin
    • , Carolina E. Caffaro
    •  & Marcos E. Milla
  • Article
    | Open Access

    This study describes a class of small molecule compounds that promote ABCA1-dependent cholesterol efflux via a non-transcriptional mechanism, the identification of the molecular target by a chemical biology approach, and the potential of these agents for the treatment of chronic kidney diseases and potentially other diseases where lipid accumulation drives disease progression.

    • Matthew B. Wright
    • , Javier Varona Santos
    •  & Alessia Fornoni
  • Article
    | Open Access

    Chronic use of mTORC1 inhibitors produces undesirable side effects in humans which limit their value for CNS disorders treatment. The authors present a binary drug strategy to protects mTORC1 activity in the periphery and show its potential utility in preclinical models of alcohol use disorder.

    • Yann Ehinger
    • , Ziyang Zhang
    •  & Dorit Ron
  • Article
    | Open Access

    Alcoholic hepatitis is characterized by intense liver inflammation driven by excessive cytokines and chemokines production and immune cell infiltration. Here the authors identify a super-enhancer that regulates the expression of multiple CXCL chemokines in alcoholic hepatitis and may be a potential therapeutic target.

    • Mengfei Liu
    • , Sheng Cao
    •  & Vijay H. Shah
  • Article
    | Open Access

    The anti-tumour effect of immune checkpoint inhibitors is potentiated by CD137 agonists in preclinical models, but translation of these results to the clinical practice is hampered by toxicity. Authors describe here a human CD137xPD-L1 bispecific antibody with improved anti-cancer activity whilst maintaining low toxicity in non-human primates.

    • Cecile Geuijen
    • , Paul Tacken
    •  & Mark Throsby
  • Article
    | Open Access

    IRF5 is a potential target for therapy in systemic lupus erythematosus (SLE). Here the authors show using mouse SLE-like models that genetic or chemical inhibition of IRF5 after SLE onset could be more effective than, or an add on for, currently utilised type I interferon inhibition.

    • Tatsuma Ban
    • , Masako Kikuchi
    •  & Tomohiko Tamura
  • Article
    | Open Access

    Toll-like receptor 8 (TLR8) plays essential roles in the innate immune response to viral single-stranded RNA (ssRNA), so small molecule modulators of TLR8 are of interest, however adverse effects limit their use. Here, the authors report a tetrasubstituted imidazole CU-CPD107 with dichotomous behaviour, which inhibits R848-induced TLR8 signaling, but shows synergistic activity in the presence of ssRNA, making it a potential antiviral agent.

    • Yi Yang
    • , Adam Csakai
    •  & Hang Yin
  • Article
    | Open Access

    Various GPCRs display constitutive ligand-independent activity, but it remains unclear whether ligand-dependent and -independent conformations differ. Here the authors demonstrate the recognition and blocking of G protein recruitment of either the ligand-bound active, or the constitutively active apo-conformation of the viral GPCR US28 by different nanobodies that target similar intracellular loops of the receptor.

    • Timo W. M. De Groof
    • , Nick D. Bergkamp
    •  & Martine J. Smit
  • Article
    | Open Access

    There is a need to optimise cryo-EM data acquisition approaches to improve the resolution of GPCR cryo-EM structures to better than 2.5 Å, in order to use them for structure-based drug design purposes. Here, the authors present a systematic analysis of the main cryo-EM experimental parameters using three GPCRs as test cases, which is also of interest for the cryo-EM structure determination of other small membrane proteins.

    • Radostin Danev
    • , Matthew Belousoff
    •  & Patrick M. Sexton
  • Article
    | Open Access

    Radiofrequency ablation (RFA) is a minimally invasive tumor ablation method, however incomplete ablation and the induction of an immunosuppressive microenvironment limit its efficacy in the clinic. Here the authors design a pH-responsive lipoxidase-loaded nanoreactor, that by triggering ferroptosis and anti-tumor immunity, amplify the therapeutic benefits of RFA in preclinical models.

    • Zhijuan Yang
    • , Yujie Zhu
    •  & Zhuang Liu
  • Article
    | Open Access

    Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.

    • Toshiko Yamazawa
    • , Takuya Kobayashi
    •  & Takashi Murayama
  • Article
    | Open Access

    Nucleoside analogs (NNA), such as acyclovir (ACV) and ganciclovir (GCV), are widely used as anti-virals to treat herpes virus infection. Here, Nishii et al. show that diphosphatase NUDT15 hydrolyzes ACV and GCV, therewith reducing NNA activity in vitro and link NUDT15 variation to inter-patient variability in ACV and GCV therapeutic effects.

    • Rina Nishii
    • , Takanori Mizuno
    •  & Jun J. Yang
  • Article
    | Open Access

    Amyloid aggregation of mutant p53 contributes to its loss of tumor suppressor function and oncogenic gain-of-function. Here, the authors use a protein mimetic to abrogate mutant p53 aggregation and rescue p53 function, which inhibits cancer cell proliferation in vitro and halts tumor growth in vivo.

    • L. Palanikumar
    • , Laura Karpauskaite
    •  & Mazin Magzoub
  • Article
    | Open Access

    Hoshino et al., engineer a human virus receptor, hACE2, and demonstrate its potential for overcoming SARS-CoV-2 mutations that otherwise hinder therapeutic interventions. Overall, the data provide insights in to the therapeutic potential of engineered receptors.

    • Yusuke Higuchi
    • , Tatsuya Suzuki
    •  & Atsushi Hoshino
  • Article
    | Open Access

    The glucagon-like peptide-1 (GLP-1) receptor is a key regulator of glucose homeostasis and a drug target for type 2 diabetes but available GLP-1R agonists are suboptimal due to several side-effects. Here authors report the cryo-EM structure of GLP-1R bound to an ago-allosteric modulator in complex with heterotrimeric Gs which offers insights into the molecular details of ago-allosterism.

    • Zhaotong Cong
    • , Li-Nan Chen
    •  & Ming-Wei Wang
  • Article
    | Open Access

    Polθ has been recently identified as a therapeutic target in cancer but specific inhibitors are currently unavailable. Here, the authors identify small molecule inhibitors of Polθ’s polymerase activity which elicit BRCA1/2 synthetic lethality, enhance the effect of PARP inhibitors and target PARP inhibitor resistance caused by 53BP1/Shieldin pathway defects.

    • Diana Zatreanu
    • , Helen M. R. Robinson
    •  & Christopher J. Lord
  • Article
    | Open Access

    SARS-CoV-2 3CL protease (3CLpro) is essential for coronavirus replication and of great interest as an antiviral drug target. Here, the authors show that the naturally occurring flavonoid myricetin is a non-peptidomimetic and covalent inhibitor of 3CLpro, and they solve crystal structures of 3CLpro with myricetin and derivatives, which reveal that the pyrogallol group covalently modifies the catalytic cysteine.

    • Haixia Su
    • , Sheng Yao
    •  & Yechun Xu
  • Article
    | Open Access

    Here, the authors provide a mechanism for an improved version of a nanoformulated myristoylated prodrug of cabotegravir (CAB), named NM2CAB, and its bioavailability, stability and pharmacokinetics in mice and rats performed in independent academic and a contracted research labs, suggesting that the extended half-life of the prodrug is not a property of enzymatic hydrolysis but rather release or dissolution of the prodrug from the nanocrystal.

    • Nagsen Gautam
    • , JoEllyn M. McMillan
    •  & Yazen Alnouti
  • Article
    | Open Access

    Partially unfolded alpha-lactalbumin forms an oleic acid complex with antitumorigenic properties. Here, the authors define a structurally flexible, peptide-based oleate complex and report a phase I/II clinical trial where this complex is used to treat patients with bladder cancer.

    • Antonín Brisuda
    • , James C. S. Ho
    •  & Catharina Svanborg
  • Article
    | Open Access

    CCR5 is a co-receptor for many transmitted HIV strains. Here, the authors show that biweekly injection of the CCR5-specific antibody Leronlimab protects rhesus macaques against infection following repeated intrarectal challenges of a CCR5-tropic SHIV.

    • Xiao L. Chang
    • , Gabriela M. Webb
    •  & Jonah B. Sacha
  • Article
    | Open Access

    Impaired wound healing is a serious complication in diabetic patients, and is associated with reduced HIF1α stability. Here, the authors design a small molecule that stabilizes HIF1α by blocking its interaction with VHL and show that it promotes wound healing in mouse models of diabetes.

    • Guodong Li
    • , Chung-Nga Ko
    •  & Chung-Hang Leung
  • Article
    | Open Access

    Metals such as calcium and potassium have long been known to regulate the diameter of arteries that control blood flow. Here, we report that zinc causes relaxation of blood vessels and reduces blood pressure by its coordinated action in sensory nerves, endothelium and smooth muscle cells.

    • Ashenafi H. Betrie
    • , James A. Brock
    •  & Scott Ayton
  • Article
    | Open Access

    The circadian clock is an internal mechanism that controls various physiological processes, such as the sleep-wake cycle, but its precise regulation is challenging. Here, the authors develop a visible light-responsive inhibitor of casein kinase I which controls the period and phase of cellular and tissue circadian rhythms in a reversible manner.

    • Dušan Kolarski
    • , Carla Miró-Vinyals
    •  & Ben L. Feringa
  • Article
    | Open Access

    Although Hippo signaling restricts regeneration in many mammalian organs, the pharmaceutical tools available to modulate the pathway have been limited. Here, the authors report a small molecule that may inhibit a key element in the Hippo cascade and may activate regenerative responses in several mammalian tissues.

    • Nathaniel Kastan
    • , Ksenia Gnedeva
    •  & A. J. Hudspeth
  • Article
    | Open Access

    Nasopharyngeal carcinoma (NPC) is a malignant cancer type with high morbidity in Asia, and its current molecular classification is insufficient to predict therapy outcomes. Here the authors explore NPC subtype-specific response to therapy with a pharmacogenomics strategy integrating genomics and drug response of patient-derived organoids.

    • Ren-Bo Ding
    • , Ping Chen
    •  & Chu-Xia Deng
  • Article
    | Open Access

    Ebselen is an organoselenium drug that inhibits the SARS-CoV-2 main protease (Mpro). Here, the authors co-crystallised Mpro with ebselen and an ebselen derivative and observed an enzyme bound organoselenium covalent adduct in the crystal structures, which was also confirmed by mass spectrometry analysis.

    • Kangsa Amporndanai
    • , Xiaoli Meng
    •  & S. Samar Hasnain
  • Article
    | Open Access

    Although enterovirus D68 poses a major global threat to children, neither vaccines nor therapeutics are currently available. Using Cryo-EM, Zhang et al. show that two murine-derived monoclonal antibodies with therapeutic efficacy neutralize virions via binding to the canyon region, creating steric hindrance for sialic acid receptor binding.

    • Chao Zhang
    • , Cong Xu
    •  & Zhong Huang
  • Article
    | Open Access

    Polymer-based systems are often considered a necessity for controlled drug delivery, but have well-known limitations. Here, the authors report on drug delivery implants formed solely from corticosteroid dimers, which demonstrate controlled release and overcome many of the challenges of polymer-based systems.

    • Kyle Battiston
    • , Ian Parrag
    •  & Wendy Naimark
  • Article
    | Open Access

    The histone methyltransferase ASH1L plays a role in various diseases, including cancer, and has been validated as a therapeutic target; however, no inhibitors of ASH1L have been reported. Here the authors present small molecule inhibitors of ASH1L and demonstrate their on-target activity in leukemia cells and a mouse model of leukemia.

    • David S. Rogawski
    • , Jing Deng
    •  & Jolanta Grembecka
  • Article
    | Open Access

    Engineered live bacteria could represent a new class of therapeutic treatment for human disease. Here, the authors use a human gut-on-a-chip microfluidics system to characterize an engineered live bacterial therapeutic, designed for the treatment of phenylketonuria, and to construct mathematical models that predict therapeutic strain function in non-human primates.

    • M. Tyler Nelson
    • , Mark R. Charbonneau
    •  & Camilla A. Mauzy
  • Article
    | Open Access

    Most oncogenic RAS mutants remain undruggable. Here, the authors developed monobodies that selectively recognize the active state of KRAS(G12V) and KRAS(G12C) and demonstrated their utility in inhibiting RAS functions through inhibition and degradation.

    • Kai Wen Teng
    • , Steven T. Tsai
    •  & Shohei Koide
  • Article
    | Open Access

    Activation of cullin-RING ligases can be inhibited by targeting DCN1, but selective DCN1 inhibitors with in vivo activity are lacking. Here, the authors develop covalent DCN1 inhibitors that selectively and potently inhibit cullin-3 activation and downstream functions in cells and in mice.

    • Haibin Zhou
    • , Jianfeng Lu
    •  & Shaomeng Wang
  • Article
    | Open Access

    Arginine addiction induced by argininosuccinate synthase (ASSN1) deficiency has been exploited to treat ASS1-deficient cancers. Here, the authors show an alternative therapeutic approach where ASS1 activity is increased by the pesticide spinosyn A and is shown to inhibit breast cancer cell proliferation.

    • Zizheng Zou
    • , Xiyuan Hu
    •  & Zhiyong Luo
  • 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