About

Professor Naoto Hoshi is a researcher at the University of California, Irvine, with a focus on the physiological role and regulation of the M-channel, a sub-threshold ion channel that influences neuronal excitability. His laboratory studies how the M-channel is modulated by various signals, particularly through the AKAP150 macromolecular complex, which integrates multiple signaling pathways. His work has demonstrated that genetic removal of AKAP150 results in tolerance to seizure induction, and his research aims to control pathological neuronal activity via M-channel modulators. His research employs molecular biology, electrophysiology, live cell FRET imaging, and behavioral neuroscience to understand the physiological and pathological roles of M-current suppression in learning, memory, and seizures. Professor Hoshi has made significant contributions to the understanding of signal transduction mechanisms involving AKAP complexes and ion channels, with findings published in prominent scientific journals.

Research topics

• Biology
• Biochemistry
• Cell biology
• Endocrinology
• Organic chemistry
• Pharmacology
• Chemistry
• Genetics
• Stereochemistry
• Medicine
• Internal medicine

Selected publications

• Structural Aspects of Proline Methanologues in Drug Design, Optimization, and Development

  The Journal of Organic Chemistry · 2026-02-20

  article1st authorCorresponding

  The primary objective of this Perspective is to highlight the potential merits of replacing a proline moiety in a drug design enterprise with a surrogate consisting of a proline that incorporates a bridged methano ring, designated as a methanologue. Emphasis is placed on the effect of the methano bridge on the conformational properties of the embedded proline within a drug molecule, and how this influences the associated geometric parameters and stereoelectronic features of the corresponding amides, which can lead to an enhancement of biological activity and metabolic stability. Thus, the 3-dimensional structures of different categories of proline methanologues delineating precisely annotated angular and interatomic distances extracted from crystallographic data are analyzed and discussed against the backdrop of their inclusion as preferred pharmacophoric elements in drug molecules. The in vitro and in vivo activities of investigational and marketed drug molecules engineered to include methylene-bridged proline units are discussed for a variety of biological targets designed to address a range of diseases related to specific human pathologies.

  PublisherDOI

• Design and Synthesis of 7-(N-Aryl Pyrrolidinyl) Indoles as Potential DCAF15 Binders

  Reactions · 2025-03-07 · 1 citations

  articleOpen accessSenior authorCorresponding

  We describe the design and synthesis of a series of 7-(N-aryl pyrrolidinyl) indoles and oxo-analogs as isosteric mimics of the DCAF15 binder E7820, a well-known member of aryl sulfonamides known as SPLAMs. The functionalization of C-7 in indoles was achieved by metal-catalyzed CH-activation with unexpected results. Binding assays revealed the pyrrolidine N-aryl carboxylic acid analog to be as equally active as E7820.

  PublisherOA PDFDOI

• Stereocontrolled Synthesis of 2S,3R-(3)-Piperidinyl Glycine and 2S,4S-(3)-Piperidinyl Alanine: Medicinally Relevant Constrained Cyclic Amino Acids

  Synthesis · 2025-08-13

  articleSenior author

  Abstract The stereocontrolled syntheses of 2S,3R-(3)-piperidinyl glycine hydrochloride and 2S,4S-(3)-piperidinyl alanine hydrochloride are described. These conformationally constrained α,γ- and α,δ-diamino acids were obtained via the stereoselective allylation of N–Cbz aspartate and glutamate diesters, respectively, followed by the intramolecular cyclization to form the piperidine ring. Orthogonally protected intermediates enabled late-stage diversification. Final deprotections afforded the target amino acids in high yields. The combination of the natural α-amino acid fragment and the basic piperidine unit in 3-piperidinyl glycine and alanine reveals the embedded frameworks of l-ornithine and l-lysine, making them peripheral or inserted components within structures of bioactive compounds of value for drug optimization and development.

  PublisherDOI

• Design and Synthesis of E7820/Tasisulam Hybrids as Potential DCAF15 Binders

  Reactions · 2025-05-20

  articleOpen accessSenior authorCorresponding

  We describe the design and synthesis of a series of N-[arylsulfonyl]-1H-pyrrole-2-carboxamides as hybrid analogs of the DCAF15 binders E7820 and tasisulam, two representative SPLAMs (sulfonamide-containing molecular glues). These hybrid molecules were designed to combine the key interactions of both parent ligands within the DCAF15 binding site, as supported by docking studies. Binding affinity was evaluated using fluorescence polarization assays, and structure–activity relationships were established, highlighting the importance of dichlorinated pyrrole moieties. Selected compounds were also tested in HCT116 cells to assess in vitro activity.

  PublisherOA PDFDOI

• Total synthesis of Asperdinones B, C, D, E and Terezine D

  2025-09-18

  preprintOpen accessSenior author

  The total synthesis of new members of prenylated indole alkaloids exhibiting α-glucosidase activity is described. Asperdinones B, C, D, and E are characterized by the presence of a 10 R 3-indolylmethyl benzodiazepine-2,5-dione unit at C-3 of the C4-C7 prenylated indoles. Methods of direct and indirect prenylation of indole and tryptophane were explored. Different approaches were adopted for functionalization of C4-C7 prenyl indoles at C3 using Negishi cross-coupling methods. The asperdinones are among the rare tryptophane-derived indole alkaloids which appear to have undergone epimerization due to genetic alteration of specific gene clusters that code for a C10 R configuration

  PublisherDOI

• Total synthesis of asperdinones B, C, D, E and terezine D

  Beilstein Journal of Organic Chemistry · 2025-12-17

  articleOpen accessSenior author

  The total synthesis of new members of prenylated indole alkaloids exhibiting α-glucosidase activity is described. Asperdinones B, C, D, and E are characterized by the presence of a (3 R )-3-indolylmethylbenzodiazepine-2,5-dione unit at C-3 of C4–C7 prenylated indoles. Methods of direct and indirect prenylation of indole and tryptophan were explored. Different approaches were adopted for the functionalization of C4–C7 prenylindoles at C-3 using Negishi cross-coupling methods. The asperdinones are among the rare tryptophan-derived indole alkaloids which appear to have undergone epimerization due to genetic alteration of specific gene clusters that code for a (3 R ) configuration.

  PublisherOA PDFDOI

• Sphingosine simultaneously inhibits nuclear import and activates PP2A by binding importins and PPP2R1A

  The EMBO Journal · 2025-06-30 · 2 citations

  articleOpen access

  Sphingosine and constrained analogs like FTY720 and SH-BC-893 restrain tumor growth through incompletely defined mechanisms that include protein phosphatase 2A (PP2A) activation. Here we show that these compounds directly bind not only the PP2A scaffolding subunit PPP2R1A, but also the structurally related karyopherins importin-β1 (KPNB1), transportin-1 (TNPO1), importin-5 (IPO5), and importin-7 (IPO7). Binding to sphingosine-like molecules triggers reversible unfolding of these target proteins, resulting in activation of PP2A and inhibition of importins. Although sphingosine engages these proteins, ceramide does not, suggesting that these two endogenous tumor-suppressive sphingolipids work through distinct mechanisms. Simultaneous PP2A activation and importin inhibition reduces nuclear levels of proteins that drive cancer progression and therapeutic resistance such as JUN, YAP, MYC, androgen receptor, hnRNPA1, and NF-κB under conditions where compounds that target PP2A or KPNB1 individually are inactive. These findings provide new insights into sphingolipid biology and highlight a possible path toward cancer therapeutics that could overcome drug resistance.

  PublisherDOI

• My 50-Plus Years of Academic Research Collaborations with Industry. A Retrospective

  The Journal of Organic Chemistry · 2024-06-12 · 1 citations

  review1st authorCorresponding

  A retrospective is presented highlighting the synthesis of selected "first-in-kind" natural products, their synthetic analogues, structure elucidations, and rationally designed bioactive synthetic compounds that were accomplished because of collaborations with past and present pharmaceutical and agrochemical companies. Medicinal chemistry projects involving structure-based design exploiting cocrystal structures of small molecules with biologically relevant enzymes, receptors, and bacterial ribosomes with synthetic small molecules leading to marketed products, clinical candidates, and novel drug prototypes were realized in collaboration. Personal reflections, historical insights, behind the scenes stories from various long-term projects are shared in this retrospective article.

  PublisherDOI

• Towards combining backbone and sugar constraint in 3′-3′ bis-phosphonate tethered 2′-4′ bridged LNA oligonucleotide trimers

  RSC Advances · 2024-01-01 · 2 citations

  articleOpen accessSenior authorCorresponding

  Therapeutic oligonucleotides are chemically modified to enhance their drug-like properties - including binding affinity for target RNA. Many nucleic acid analogs that enhance RNA binding affinity constrain the furanose sugar in an RNA-like sugar pucker. The improvements in binding affinity result primarily from increased off-rates with minimal effects on on-rates for hybridization. To identify alternate chemical modification strategies that can modulate on- and off-rates for oligonucleotide hybridization, we hypothesized that extending conformational restraint across multiple nucleotides could modulate hybridization kinetics by restricting rotational freedom of the sugar-phosphate backbone. As part of that effort, we recently reported that using hydrocarbon tethers to bridge adjacent phosphodiester linkages as phosphonate tethered bridges can pre-organize nucleic acids in conformations conducive for Watson-Crick base-pairing and modulate hybridization kinetics. In this report, we describe the synthesis of locked nucleic acid (LNA) trimers linked through alkylphosphonate tethers which restrict conformation of the furanose sugar in addition to restricting conformational mobility of the sugar-phosphate backbone across three nucleotide units.

  PublisherOA PDFDOI

• Revisiting the dipeptidyl carboxypeptidase inhibitor captopril as a source of pan anti-trypanosomatid agents

  Bioorganic & Medicinal Chemistry Letters · 2024-07-14 · 2 citations

  articleSenior authorCorresponding
  PublisherDOI

Recent grants

• NIH Grant R21CA178230

  NIH · $338k · 2016

Frequent coauthors

• B. Deschenes-Simard

  Université de Montréal

  40 shared

• Stéphane Dorich

  40 shared

• Gilles Berger

  Université Libre de Bruxelles

  39 shared

• Éric Westhof

  Architecture et Réactivité de l'arN

  36 shared

• Nicolas Moitessier

  McGill University

  34 shared

• Youssef L. Bennani

  Université Mohammed VI des Sciences de la Santé

  33 shared

• Eric E. Swayze

  University of Tennessee Health Science Center

  30 shared

• Éric Therrien

  Schrodinger (United States)

  25 shared

Labs

• THE HANESSIAN GROUPPI

  Not provided

Education

• M.D.

  Kanazawa University School of Medicine

  1990

• Ph.D.

  Kanazawa University Graduate School of Medicine

  1999

Awards & honors

• Juzen alumni award for young scientist (2000)
• Young scientist award from Uehara memorial foundation (2004)
• Juzen Medical award (2007)