Drug discovery and development articles within Nature Communications

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  • 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

    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

    Polyketide macrolides are of interest for drug discovery but their inherent structural and stereochemical complexity hinders the exploration of related regions of chemical space more broadly. Here, the authors designed in silico and synthesized a library of tetrahydrofuran-containing polyketide macrolides, and screened them against a panel of biological assays, identifying biologically active library members.

    • Darryl M. Wilson
    • , Daniel J. Driedger
    •  & Robert A. Britton

  • Article
    | Open Access

    Tetrodotoxin and congeners are specific voltage-gated sodium channel blockers that exhibit remarkable anesthetic and analgesic effects but total synthesis procedures are often limited by the scale. Here, the authors present a scalable asymmetric syntheses of Tetrodotoxin and 9-epiTetrodotoxin from the abundant chemical feedstock furfuryl alcohol.

    • Peihao Chen
    • , Jing Wang
    •  & Xiangbing Qi

  • Article
    | Open Access

    Regioselectivity prediction for many reactions remains a challenging target for a priori prediction. Here, the authors develop a machine learning model that predicts the outcomes of Minisci reactions.

    • Emma King-Smith
    • , Felix A. Faber
    •  & Alpha A. Lee

  • Article
    | Open Access

    While carbon-introducing difunctionalization of C-C double bonds is well established, the analogous difunctionalization for introducing germanium group and other functionalities remains elusive. Here, the authors describe a nickel-catalyzed germylative alkylation of activated olefins with easily accessible primary, secondary and tertiary alkyl bromides and chlorogermanes as the electrophiles to form C-Ge and C-Calkyl bonds simultaneously.

    • Rui Gu
    • , Xiujuan Feng
    •  & Xuan Zhang

  • Article
    | Open Access

    Traditional metallaphotocatalysis often requires two or more separate catalysts and is considered to be costly and not tolerant towards a wide substrate scope. Here the authors realize metallaphotocatalysis with a bifunctional dirhodium tetracarboxylate as single catalyst component to merge carbenoid chemistry and 1O2 chemistry.

    • Taoda Shi
    • , Tianyuan Zhang
    •  & Wenhao Hu

  • Article
    | Open Access

    Chemo-activation of mitochondrial ClpP exhibits promising anticancer properties. Here, the authors develop a potent activator ZK53 that is highly selective on human ClpP but inactive toward bacterial ClpP proteins, and show that ZK53 causes cell cycle arrest via ClpP on lung squamous cell carcinoma cells and exhibits therapeutic effects in animal models.

    • Lin-Lin Zhou
    • , Tao Zhang
    •  & Cai-Guang Yang

  • Article
    | Open Access

    Designing novel molecules with desired bioactivity is a critical challenge in drug discovery, particularly for novel or understudied targets. The authors propose a pharmacophore-guided deep learning approach PGMG to generate diverse active-like molecules with limited activity data.

    • Huimin Zhu
    • , Renyi Zhou
    •  & Min Li

  • Article
    | Open Access

    The phenyl ring is a basic structural element in chemistry. Here, the authors show the design, synthesis, and validation of 2-oxabicyclo[2.2.2]octane as a new saturated bioisostere with improved physicochemical properties

    • Vadym V. Levterov
    • , Yaroslav Panasiuk
    •  & Pavel K. Mykhailiuk

  • Article
    | Open Access

    The Mannich reaction is a well-established method for the synthesis of β-amino carbonyl compounds while the analogous reactions of homo-enol or its equivalents with imines or iminium ions are much less explored. Here, the authors describe a homo-Mannich reaction of cyclopropanol with imines generated via a Bischler-Napieralski reaction.

    • Hanyue Qiu
    • , Xinghai Fei
    •  & Min Zhang

  • Article
    | Open Access

    The lack of efficient and diverse synthesis strategy has hindered the study of perifused cycles. Here, the authors report a metal-catalyzed cascade electrocyclization to access 5,6,7-perifused cycles, and demonstrated the versatility of this protocol in the late-stage modification of pharmaceuticals.

    • Jingpeng Han
    • , Yongjian Yang
    •  & Baosheng Li

  • Article
    | Open Access

    Most DNA-encoded library (DEL) syntheses are limited by the presence of sensitive DNA-based constructs. Here, the authors develop DOSEDO, a diverse 3.7 million compound DEL, generated through diversity-oriented synthesis that provides enhanced scaffold and exit vector diversity and gives validated binding hits for multiple protein targets.

    • Liam Hudson
    • , Jeremy W. Mason
    •  & Karin Briner

  • Article
    | Open Access

    Branched chain ketoacid dehydrogenase kinase (BDK) inhibits the activity of branched chain ketoacid dehydrogenase and branched chain amino acid degradation, implicated in several diseases. Here, the authors discover a BDK inhibitor and degrader that shows efficacy in rodent metabolism and heart failure models, as well as another class of BDK inhibitors that stabilizes BDK.

    • Rachel J. Roth Flach
    • , Eliza Bollinger
    •  & Kevin J. Filipski

  • Article
    | Open Access

    The lack of a universal platform for PROTAC development remains a major bottleneck. Here, the authors report modular DNA framework-based PROTACs (DbTACs) that enable precise control of the linker length and selective degradation of diverse targets in different cellular compartments using various warheads.

    • Li Zhou
    • , Bin Yu
    •  & Yi Ma

  • Article
    | Open Access

    Deoxycytidine kinase is the rate-limiting enzyme of the salvage pathway and it has recently emerged as a target for antiproliferative therapies for cancers where it is essential. Here, the authors develop a potent inhibitor applying an iterative multidisciplinary approach, which relies on computational design coupled with experimental evaluations.

    • Magali Saez-Ayala
    • , Laurent Hoffer
    •  & Xavier Morelli

  • Article
    | Open Access

    The development of direct-acting antivirals to combat COVID-19 remains an important goal. Here the authors design covalent inhibitors that target the papain-like protease from SARS-CoV-2. The most promising inhibitor blocks viral replication in mammalian cells.

    • Brian C. Sanders
    • , Suman Pokhrel
    •  & Jerry M. Parks

  • Article
    | Open Access

    Engineering excitation wavelength of photosensitizers allows to enhanced reactive oxygen species but controlling the wavelength corresponding to operating conditions remains challenging. Here, the authors implement a wavelength-engineerable imidazolium-based porous organic polymer and demonstrate tuning of the optimal wavelength for maximum performance by modifying the linker system.

    • Jinwoo Shin
    • , Dong Won Kang
    •  & Chang Seop Hong

  • Article
    | Open Access

    Treatment of hypertension entails use of angiotensin-converting enzyme inhibitors. Here, the authors show a series of karnamicins with significant inhibitory activity and identify two unusual flavoprotein hydroxylases involved in the assembly of the fully-substituted hydroxypyridine core of karnamicins.

    • Zhiyin Yu
    • , Jian-Ping Huang
    •  & Sheng-Xiong Huang

  • Article
    | Open Access

    MraY is a membrane enzyme required for bacterial cell wall synthesis. Here, the authors modify sphaerimicins as antibacterials targeting it via structure-based design and synthesis through two key reactions, showing a platform for further development of MraY inhibitors as antibacterials.

    • Takeshi Nakaya
    • , Miyuki Yabe
    •  & Satoshi Ichikawa

  • Article
    | Open Access

    Retrieval of a new starting active compound with a novel scaffold during early drug development is an important but challenging task. Here, the authors propose a generative deep learning model and by applying this model they discover a potent and highly selective RIPK1 inhibitor with a previously unreported scaffold.

    • Yueshan Li
    • , Liting Zhang
    •  & Shengyong Yang

  • Article
    | Open Access

    Tuberculosis is a major cause of mortality, and the rise of drug-resistant strains of Mycobacterium tuberculosis requires the urgent development of safe and effective treatments. In this work, the authors develop a compound against lysyl-tRNA synthetase, demonstrating on-target mechanism of action and efficacy in vivo.

    • Simon R. Green
    • , Susan H. Davis
    •  & Laura A. T. Cleghorn

  • Article
    | Open Access

    Therapeutic modulation of the complement system has gained interest over the past two decades. Here, the authors provide molecular-level insight into the mode-of-action, target selectivity and species specificity of the compstatin family of complement inhibitors, which entered the clinic in 2021.

    • Christina Lamers
    • , Xiaoguang Xue
    •  & Daniel Ricklin

  • Article
    | Open Access

    The development of antimalarials against the human liver and asexual blood stages is one of the top public health challenges. Here, the authors report a single-step biochemical assay for the characterization of prolyl-tRNA synthetase inhibitors, and develop high-affinity inhibitors for the enzyme, including elusive triple-site ligands.

    • Mark A. Tye
    • , N. Connor Payne
    •  & Ralph Mazitschek

  • Article
    | Open Access

    Inhibiting alpha-synuclein self-assembly into amyloid structures, associated with Parkinson’s disease, is a potential therapeutic intervention. Here, the authors identify the domains/sequences that are essential for alpha-synuclein aggregation and test the activity of foldamer-based antagonists to identify potential therapeutic targets.

    • Jemil Ahmed
    • , Tessa C. Fitch
    •  & Sunil Kumar

  • Article
    | Open Access

    Polymyxins are often the last therapeutic option for multidrug-resistant (MDR) bacteria, but have suboptimal safety and efficacy. Here the authors report the discovery and development of a synthetic lipopeptide with an improved safety and efficacy against top-priority MDR Gram-negative pathogens.

    • Kade D. Roberts
    • , Yan Zhu
    •  & Jian Li

  • Article
    | Open Access

    Disruption of CREB/CRTC2, a key gluconeogenic transcriptional complex, has been shown to ameliorate insulin resistance in mice. Here, the authors show that the inhibitor artipllin C and the synthetic compound A57, which presents with higher inhibitory activity, improve insulin sensitivity in obese mice by inhibiting CREB-CRTC2 interaction.

    • Yaqiong Chen
    • , Jiang Wang
    •  & Yi Liu

  • Article
    | Open Access

    Efflux transporters of the RND family confer resistance to multiple antibiotics in Gram-negative bacteria. Here, the authors identify pyridylpiperazine-based compounds that potentiate antibiotic activity in E. coli through allosteric inhibition of its primary RND transporter.

    • Coline Plé
    • , Heng-Keat Tam
    •  & Ruben C. Hartkoorn

  • Article
    | Open Access

    Considering the intrinsic toxicities of transition metals, their incorporation into drug therapies must operate at minimal amounts while ensuring adequate catalytic activity within complex biological systems. This study investigates the design of synthetic prodrugs that not only can be tuned to be harmless, but are robustly transformed in vivo to reach therapeutically relevant levels.

    • Igor Nasibullin
    • , Ivan Smirnov
    •  & Katsunori Tanaka

  • Article
    | Open Access

    Aberrant expression of fucosylated glycans has been linked to several disease states. Control of fucose expression on live cells is needed to aid research and therapy development. Here the authors report on the development of a class of fucosylation metabolic prodrug inhibitors and demonstrated inhibition of cellular fucosylation.

    • Johan F. A. Pijnenborg
    • , Emiel Rossing
    •  & Thomas J. Boltje

  • 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

    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

    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

  • Review Article
    | Open Access

    Natural products are an important source of bioactive compounds and have versatile applications in different fields, but their discovery is challenging. Here, the authors review the recent developments in genome mining for discovery of natural products, focusing on compounds from unconventional microorganisms and microbiomes.

    • Kirstin Scherlach
    •  & Christian Hertweck

  • Article
    | Open Access

    Fragment-based drug discovery employs screening of small polar compounds typically exhibiting low affinity towards protein targets. Here, the authors combine the use of protein-based binding pharmacophores with the theory of protein hotspots to develop a design protocol for fragment libraries, called SpotXplorer, and validate their approach on common and emerging drug targets.

    • Dávid Bajusz
    • , Warren S. Wade
    •  & György M. Keserű

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