bims-cepepe Biomed News
on Cell-penetrating peptides
Issue of 2024‒09‒15
sixteen papers selected by
Henry Lamb, Queensland University of Technology
  1. cPEPmatch Webserver: A comprehensive tool and database to aid rational design of cyclic peptides for drug discovery.
  2. Triscysteine disulfide-directing motifs enabling design and discovery of multicyclic peptide binders.
  3. Target-Specific De Novo Peptide Binder Design with DiffPepBuilder.
  4. Inhibition of the EphA2-Sam/Ship2-Sam Association through Peptide Ligands: Studying the Combined Effect of Charge and Aromatic Character.
  5. A venom peptide-induced NaV channel modulation mechanism involving the interplay between fixed channel charges and ionic gradients.
  6. Characteristics of membrane transport, metabolism, and target protein binding of cyclic depsipeptide destruxin E in HeLa cells.
  7. Protocol for detecting lysosome quantity and membrane permeability in acute myeloid leukemia cell lines.
  8. Introducing Chemoselective Peptide Conjugation via N-Alkylation of Pyridyl-alanine: Solution and Solid Phase Applications.
  9. Substrate interactions guide cyclase engineering and lasso peptide diversification.
  10. Structure, Function, and Activity of Small Molecule and Peptide Inhibitors of Protein Arginine Methyltransferase 1.
  11. Dually Labeled Neurotensin NTS1R Ligands for Probing Radiochemical and Fluorescence-Based Binding Assays.
  12. Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I.
  13. Integrating amino acids into Bcr-Abl inhibitors: design, synthesis, biological evaluation, and in silico studies.
  14. Rapid Production of Native and Mirror-Image Tumor Necrosis Factor-α Enabled by Automated Flow Peptide Synthesis Technology.
  15. Preclinical Evaluation of 177Lu-OncoFAP-23, a Multivalent FAP-Targeted Radiopharmaceutical Therapeutic for Solid Tumors.
  16. Biostructural, biochemical and biophysical studies of mutant IDH1.
  1. Comput Struct Biotechnol J. 2024 Dec;23 3155-3162
    cPEPmatch Webserver: A comprehensive tool and database to aid rational design of cyclic peptides for drug discovery.
    Brianda L Santini, Stephanie Wendel, Niklas Halbwedl, Asha Knipp, Martin Zacharias.
      Cyclic peptides have emerged as versatile scaffolds in drug discovery due to their stability and specificity. Here, we present the cPEPmatch webserver (accessible at https://t38webservices.nat.tum.de/cpepmatch/), an easy-to-use interface for the rational design of cyclic peptides targeting protein-protein interactions combined with a semi-quantitative evaluation of binding stability. This platform also offers access to a comprehensive database of cyclic peptide crystal structures. We demonstrate the webserver's utility through a series of case studies involving medically relevant protein systems, highlighting its potential to significantly advance drug discovery efforts.
    Keywords:  Cyclic peptides; Molecular dynamics; Protein binding modulation; Protein-protein complexes; Rational drug design
    DOI:  https://doi.org/10.1016/j.csbj.2024.08.008
  2. Nat Commun. 2024 Sep 06. 15(1): 7799
    Triscysteine disulfide-directing motifs enabling design and discovery of multicyclic peptide binders.
    Zengping Duan, Chuilian Kong, Shihui Fan, Chuanliu Wu.
      Peptides are valuable for therapeutic development, with multicyclic peptides showing promise in mimicking antigen-binding potency of antibodies. However, our capability to engineer multicyclic peptide scaffolds, particularly for the construction of large combinatorial libraries, is still limited. Here, we study the interplay of disulfide pairing between three biscysteine motifs, and designed a range of triscysteine motifs with unique disulfide-directing capability for regulating the oxidative folding of multicyclic peptides. We demonstrate that incorporating these motifs into random sequences allows the design of disulfide-directed multicyclic peptide (DDMP) libraries with up to four disulfide bonds, which have been applied for the successful discovery of peptide binders with nanomolar affinity to several challenging targets. This study encourages the use of more diverse disulfide-directing motifs for creating multicyclic peptide libraries and opens an avenue for discovering functional peptides in sequence and structural space beyond existing peptide scaffolds, potentially advancing the field of peptide drug discovery.
    DOI:  https://doi.org/10.1038/s41467-024-51723-w
  3. J Chem Inf Model. 2024 Sep 12.
    Target-Specific De Novo Peptide Binder Design with DiffPepBuilder.
    Fanhao Wang, Yuzhe Wang, Laiyi Feng, Changsheng Zhang, Luhua Lai.
      Despite the exciting progress in target-specific de novo protein binder design, peptide binder design remains challenging due to the flexibility of peptide structures and the scarcity of protein-peptide complex structure data. In this study, we curated a large synthetic data set, referred to as PepPC-F, from the abundant protein-protein interface data and developed DiffPepBuilder, a de novo target-specific peptide binder generation method that utilizes an SE(3)-equivariant diffusion model trained on PepPC-F to codesign peptide sequences and structures. DiffPepBuilder also introduces disulfide bonds to stabilize the generated peptide structures. We tested DiffPepBuilder on 30 experimentally verified strong peptide binders with available protein-peptide complex structures. DiffPepBuilder was able to effectively recall the native structures and sequences of the peptide ligands and to generate novel peptide binders with improved binding free energy. We subsequently conducted de novo generation case studies on three targets. In both the regeneration test and case studies, DiffPepBuilder outperformed AfDesign and RFdiffusion coupled with ProteinMPNN, in terms of sequence and structure recall, interface quality, and structural diversity. Molecular dynamics simulations confirmed that the introduction of disulfide bonds enhanced the structural rigidity and binding performance of the generated peptides. As a general peptide binder de novo design tool, DiffPepBuilder can be used to design peptide binders for given protein targets with three-dimensional and binding site information.
    DOI:  https://doi.org/10.1021/acs.jcim.4c00975
  4. J Med Chem. 2024 Sep 11.
    Inhibition of the EphA2-Sam/Ship2-Sam Association through Peptide Ligands: Studying the Combined Effect of Charge and Aromatic Character.
    Marian Vincenzi, Flavia A Mercurio, Rosanna Palumbo, Sara La Manna, Luciano Pirone, Daniela Marasco, Emilia M Pedone, Marilisa Leone.
      The Sam (sterile alpha motif) domain from the lipid phosphatase Ship2 binds the Sam domain from the EphA2 receptor to negatively regulate receptor endocytosis and degradation. This interaction is primarily linked to pro-oncogenic effects. We report on the design and evaluation of EphA2-Sam/Ship2-Sam peptide inhibitors provided with positive charges and different aromatic characters. Starting from the sequence of previously identified Ship2-Sam targeting peptides, an in silico approach was set up to predict higher affinity peptide ligands. A few peptides were experimentally tested through an interdisciplinary approach. Interaction studies were performed by nuclear magnetic resonance spectroscopy and biolayer interferometry. 3D models of Ship2-Sam/peptide complexes were predicted by AlphaFold2. Cell-based assays were carried out to investigate whether such peptide sequences might have an influence on EphA2 signaling. The approach led to the identification of novel Ship2-Sam ligands and shed further light on original approaches to design inhibitors of the Ship2-Sam/EphA2-Sam interaction.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c01459
  5. J Biol Chem. 2024 Sep 09. pii: S0021-9258(24)02258-0. [Epub ahead of print] 107757
    A venom peptide-induced NaV channel modulation mechanism involving the interplay between fixed channel charges and ionic gradients.
    Ashvriya Thapa, Jia Hao Beh, Samuel D Robinson, Jennifer R Deuis, Hue Tran, Irina Vetter, Angelo Keramidas.
      Venoms are used by arthropods either to immobilise prey or as defence against predators. Our study focuses on the venom peptide, Ta3a, from the African ant species, Tetramorium africanum and its effects on voltage-gated sodium (NaV) channels, which are ion channels responsible for the generation of electrical signals in electrically excitable cells, such as neurons. Using the NaV1.7 isoform as our model NaV channel we show that Ta3a prolongs single channel active periods with increased open probability and induces non-inactivating whole-cell currents. Ta3a-affected NaV1.7 channels exhibit a leftward (hyperpolarising) shift in activation threshold, constitutive activity even in the absence of an activating voltage stimulus, and at cell membrane voltages where channels are normally silent. Current-voltage experiments show that Ta3a shifts the voltage at which NaV current changes direction (reversal potential) by altering the local ionic concentration of permeant ions (Na+) rather than changing the channel's preference for ionic species. We propose a model where Ta3a maintains the positively charged voltage-sensing (S4) domains of the channel in the activated configuration where their electric field is exposed to the extracellular membrane surface to create an ionic bilayer comprising S4 domains and mobile anions (Cl-). This bilayer has a depolarising effect on the cell membrane, thus reducing the amount of externally applied voltage required for channel activation.
    Keywords:  biophysics; channel activation; neurotoxin; pain; peptides; sodium channel
    DOI:  https://doi.org/10.1016/j.jbc.2024.107757
  6. Drug Metab Pharmacokinet. 2024 Jul 02. pii: S1347-4367(24)00034-X. [Epub ahead of print]58 101028
    Characteristics of membrane transport, metabolism, and target protein binding of cyclic depsipeptide destruxin E in HeLa cells.
    Makoto Amifuji, Mai Inagaki, Masahito Yoshida, Takayuki Doi, Masanori Tachikawa.
      Cyclic peptides have attracted attention as new modalities for drug development owing to their unique pharmacokinetic and pharmacodynamic properties. Destruxin E, a 19-membered cyclodepsipeptide, is a promising candidate drug for cancer therapy. The purpose of the present study was to clarify the molecular mechanisms underlying membrane transport, metabolism, and the binding for target molecules of destruxin E in human cervical carcinoma HeLa cells used as a model of cancer cells. The influx transport and the intracellular metabolism of destruxin E were non-saturable and saturable, respectively, at up to 10 μM. The intracellular amounts of destruxin E and destruxin E-diol after incubation of destruxin E with the cells significantly decreased at 4 °C compared to those at 37 °C. Destruxin E-diol, but not destruxin E, undergoes efflux transport out of cells via P-gp/MDR1/ABCB1 and BCRP/ABCG2. The epoxide hydrolase EPHX2 functions as a potent metabolizing enzyme that can convert the epoxide of destruxin E to the destruxin E-diol. Treatment with an EPHX2 inhibitor increased the intracellular destruxin E levels and enhanced the inhibitory activity of vacuolar type-H+ ATPase. These results suggest that epoxide hydrolase could be a regulatory factor for intracellular destruxin E levels and its pharmacological activity.
    Keywords:  Cyclic peptide; Destruxin E; Efflux transporter; Epoxide hydrolase; Vacuolar type-H(+) ATPase
    DOI:  https://doi.org/10.1016/j.dmpk.2024.101028
  7. STAR Protoc. 2024 Sep 12. pii: S2666-1667(24)00474-X. [Epub ahead of print]5(3): 103309
    Protocol for detecting lysosome quantity and membrane permeability in acute myeloid leukemia cell lines.
    Kexiu Huang, Xinya Jiang, Juan Du, Hui Zeng.
      Lysosomal function and activity are essential to support cellular adaptation to multiple stresses. For example, certain drugs can induce increased lysosomal membrane permeability to exert their anti-cancer effects. Here, we present a protocol to evaluate the lysosome alterations induced by drug treatment. We first describe the steps for inducing lysosomal alterations in cultured cells. We then show how to quantify the number of lysosomes, assess the integrity of lysosomal membranes, and determine lysosomal membrane permeabilization by using galectin puncta assay. For complete details on the use and execution of this protocol, please refer to Jiang et al.1.
    Keywords:  cancer; cell biology; cell culture; flow cytometry
    DOI:  https://doi.org/10.1016/j.xpro.2024.103309
  8. Org Lett. 2024 Sep 13.
    Introducing Chemoselective Peptide Conjugation via N-Alkylation of Pyridyl-alanine: Solution and Solid Phase Applications.
    Soumit Dutta, Arnab Chowdhury, Anupam Bandyopadhyay.
      A novel chemoselective peptide conjugation via late-stage N-alkylation of pyridyl-alanine (PAL) in the solution and solid phase, namely, NAP, is demonstrated. The method constructs functionally diverse and highly stable N-alkylated conjugates with various peptides. Notably, conjugations in the solid phase offered a more economical process. The method can provide the opportunity for dual labeling along with a cysteine handle in a peptide chain. Finally, we showcased that the antiproliferative activities of the p53 peptide (MDM2 inhibitor) could be 2-fold enhanced via NAP conjugation with the RGD peptide (selective integrin binder).
    DOI:  https://doi.org/10.1021/acs.orglett.4c03168
  9. Nat Chem Biol. 2024 Sep 11.
    Substrate interactions guide cyclase engineering and lasso peptide diversification.
    Susanna E Barrett, Song Yin, Peter Jordan, John K Brunson, Jessica Gordon-Nunez, Gabriella Costa Machado da Cruz, Christopher Rosario, Bethany K Okada, Kelsey Anderson, Thomas A Pires, Ruoyang Wang, Diwakar Shukla, Mark J Burk, Douglas A Mitchell.
      Lasso peptides are a diverse class of naturally occurring, highly stable molecules kinetically trapped in a distinctive [1]rotaxane conformation. How the ATP-dependent lasso cyclase constrains a relatively unstructured substrate peptide into a low entropy product has remained a mystery owing to poor enzyme stability and activity in vitro. In this study, we combined substrate tolerance data with structural predictions, bioinformatic analysis, molecular dynamics simulations and mutational scanning to construct a model for the three-dimensional orientation of the substrate peptide in the lasso cyclase active site. Predicted peptide cyclase molecular contacts were validated by rationally engineering multiple, phylogenetically diverse lasso cyclases to accept substrates rejected by the wild-type enzymes. Finally, we demonstrate the utility of lasso cyclase engineering by robustly producing previously inaccessible variants that tightly bind to integrin αvβ8, which is a primary activator of transforming growth factor β and, thus, an important anti-cancer target.
    DOI:  https://doi.org/10.1038/s41589-024-01727-w
  10. J Med Chem. 2024 Sep 09.
    Structure, Function, and Activity of Small Molecule and Peptide Inhibitors of Protein Arginine Methyltransferase 1.
    Thordur Hendrickson-Rebizant, Sadhana R N Sudhakar, Michael J Rowley, Adam Frankel, James R Davie, Ted M Lakowski.
      Protein arginine N-methyltransferases (PRMT) are a family of S-adenosyl-l-methionine (SAM)-dependent enzymes that transfer methyl-groups to the ω-N of arginyl residues in proteins. PRMTs are involved in regulating gene expression, RNA splicing, and other activities. PRMT1 is responsible for most cellular arginine methylation, and its dysregulation is involved in many cancers. Accordingly, many groups have targeted PRMT1 using small molecules and peptide inhibitors. In this Perspective, we discuss the structure and function of selected peptide and small molecule inhibitors of PRMT1. We examine inhibitors that target the substrate arginyl peptide, SAM, or both binding sites, and the type of inhibition that results. Small molecules, and peptides that are bisubstrate, and/or PRMT transition state mimic inhibitors as well as inhibitors that alkylate PRMTs will be discussed. We define a structure-activity relationship for the aromatic/heteroaromatic N-methylethylenediamine inhibitors of PRMT1 and review current progress of PRMT1 inhibitors in clinical trials.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c00490
  11. J Med Chem. 2024 Sep 11.
    Dually Labeled Neurotensin NTS1R Ligands for Probing Radiochemical and Fluorescence-Based Binding Assays.
    Fabian J Ertl, Sergei Kopanchuk, Nicola C Dijon, Santa Veikšina, Maris-Johanna Tahk, Tõnis Laasfeld, Franziska Schettler, Albert O Gattor, Harald Hübner, Nataliya Archipowa, Johannes Köckenberger, Markus R Heinrich, Peter Gmeiner, Roger J Kutta, Nicholas D Holliday, Ago Rinken, Max Keller.
      The determination of ligand-receptor binding affinities plays a key role in the development process of pharmaceuticals. While the classical radiochemical binding assay uses radioligands, fluorescence-based binding assays require fluorescent probes. Usually, radio- and fluorescence-labeled ligands are dissimilar in terms of structure and bioactivity, and can be used in either radiochemical or fluorescence-based assays. Aiming for a close comparison of both assay types, we synthesized tritiated fluorescent neurotensin receptor ligands ([3H]13, [3H]18) and their nontritiated analogues (13, 18). The labeled probes were studied in radiochemical and fluorescence-based (high-content imaging, flow cytometry, fluorescence anisotropy) binding assays. Equilibrium saturation binding yielded well-comparable ligand-receptor affinities, indicating that all these setups can be used for the screening of new drugs. In contrast, discrepancies were found in the kinetic behavior of the probes, which can be attributed to technical differences of the methods and require further studies with respect to the elucidation of the underlying mechanisms.
    DOI:  https://doi.org/10.1021/acs.jmedchem.4c01470
  12. bioRxiv. 2024 Aug 28. pii: 2024.08.27.609828. [Epub ahead of print]
    Structural basis of inhibition of human NaV1.8 by the tarantula venom peptide Protoxin-I.
    Bryan Neumann, Stephen McCarthy, Shane Gonen.
      Voltage-gated sodium channels (NaVs) selectively permit diffusion of sodium ions across the cell membrane and, in excitable cells, are responsible for propagating action potentials. One of the nine human NaV isoforms, NaV1.8, is a promising target for analgesics, and selective inhibitors are of interest as therapeutics. One such inhibitor, the gating-modifier peptide Protoxin-I derived from tarantula venom, blocks channel opening by shifting the activation voltage threshold to more depolarised potentials, but the structural basis for this inhibition has not previously been determined. Using monolayer graphene grids, we report the cryogenic electron microscopy structures of full-length human apo-NaV1.8 and the Protoxin-I-bound complex at 3.1 Å and 2.8 Å resolution, respectively. The apo structure shows an unexpected movement of the Domain I S4-S5 helix, and VSDI was unresolvable. We find that Protoxin-I binds to and displaces the VSDII S3-S4 linker, hindering translocation of the S4II helix during activation.
    Keywords:  NaV1.8; Protoxin-I; cryoEM; graphene; voltage-gated sodium channel
    DOI:  https://doi.org/10.1101/2024.08.27.609828
  13. RSC Med Chem. 2024 Jul 24.
    Integrating amino acids into Bcr-Abl inhibitors: design, synthesis, biological evaluation, and in silico studies.
    Yuying Liu, Zeyu Yang, Jie Zhang, Na Guo, Nanxin Liu, Qingqing Zhang, Xintao Dang, Yanchen Li, Jie Zhang, Xiaoyan Pan.
      Bcr-Abl is successfully applied to drug discovery as a CML therapeutic target, but point mutation resistance has become a major challenge in the clinical treatment of CML. Our previous studies have shown that the introduction of amino acids as flexible linkers and heterocyclic structures as HBMs can achieve potent inhibition of Bcr-AblT315I. In continuation of these studies, we further enriched the linker types by developing a library of compounds with tert-leucine or serine as a linker. Biological results showed that these compounds exhibited enhanced inhibition against Bcr-AblWT and Bcr-AblT315I kinases as well as improved antiproliferative activity in leukemia cell assays compared to previously disclosed compounds. In particular, compounds TL8, TL10, BS4, BS10, SR5 and SR11 exhibited potent inhibitory activities against Ba/F3 cells bearing a T315I mutant. Additionally, compounds TL8, BS4 and SR5 effectively induced K562 cell apoptosis, arrested the cell cycle at the S or G2/M phase, and inhibited the phosphorylation of Bcr-Abl and STAT5 in a dose-dependent manner. Docking studies verified the rationality of tert-leucine or serine as a flexible linker and indicated that phenylpyridine with an amide side chain favored the potency of these inhibitors. Moreover, ADME prediction suggested that the tested compounds had a favorable safety profile. Thus, tert-leucine or serine can be used as a promising class of flexible linkers for Bcr-Abl inhibitors with heterocyclic structures as HBMs, and compounds BS4, SR5, and especially TL8, can be used as starting points for further optimization.
    DOI:  https://doi.org/10.1039/d4md00417e
  14. J Org Chem. 2024 Sep 10.
    Rapid Production of Native and Mirror-Image Tumor Necrosis Factor-α Enabled by Automated Flow Peptide Synthesis Technology.
    Ahmet Yesilcimen, Alex J Callahan, Tara L Travaline, Satish Gandhesiri, Olena S Tokareva, Andrei Loas, John H McGee, Bradley L Pentelute.
      Tumor necrosis factor-α (TNF-α) plays a central role in immune response regulation. Because elevated TNF-α production is correlated with a range of diseases, inhibiting the interaction of this protein with its native receptors has been thoroughly explored as a therapeutic avenue. Despite advancements in the development of TNF-α inhibitors, concerns remain regarding immunogenicity and loss of activity in vivo. To facilitate the discovery of stable and less immunogenic therapeutic modalities, we applied a single-shot automated fast-flow peptide synthesis (AFPS) strategy to produce full-length TNF-α, resulting in a complex reaction mixture. Leveraging the ability of AFPS to generate long peptides with high purity, we combined this technology with native chemical ligation (NCL). An NCL reaction using two fragments readily produced by AFPS afforded synthetic L- and D-TNF-α in milligram quantities (up to 5.5 mg, ∼28% yield). Following the oxidative folding of synthetic TNF-α using established conditions, higher molecular weight species were generated. Through high-throughput screening of refolding conditions, functional synthetic L- and mirror-image D-TNF-α were obtained, exhibiting characteristics analogous to those of the recombinant TNF-α. Overall, this approach can serve as a general protocol for accessing proteins that are intractable by modern protein synthesis methods, therefore, streamlining the development of novel therapeutics.
    DOI:  https://doi.org/10.1021/acs.joc.4c01866
  15. J Nucl Med. 2024 Sep 12. pii: jnumed.124.268200. [Epub ahead of print]
    Preclinical Evaluation of 177Lu-OncoFAP-23, a Multivalent FAP-Targeted Radiopharmaceutical Therapeutic for Solid Tumors.
    Andrea Galbiati, Matilde Bocci, Domenico Ravazza, Jacqueline Mock, Ettore Gilardoni, Dario Neri, Samuele Cazzamalli.
      Fibroblast activation protein (FAP) is abundantly expressed in the stroma of most human solid tumors. Clinical-stage radiolabeled FAP ligands are increasingly used as tools for the detection of various cancer lesions. To unleash the full therapeutic potential of FAP-targeting agents, ligands need to remain at the tumor site for several days after administration. We recently described the discovery of OncoFAP, a high-affinity small organic ligand of FAP with a rapid accumulation in tumors and low uptake in healthy tissues in cancer patients. Trimerization of OncoFAP provided a derivative (named TriOncoFAP, or OncoFAP-23) with improved FAP affinity. In this work, we evaluated the tissue biodistribution profile and the therapeutic performance of OncoFAP-23 in tumor-bearing mice. Methods: OncoFAP-23 was radiolabeled with the theranostic radionuclide 177Lu. Preclinical experiments were conducted on mice bearing SK-RC-52.hFAP (BALB/c nude mice) or CT-26.hFAP (BALB/c mice) tumors. 177Lu-OncoFAP and 177Lu-FAP-2286 were included in the biodistribution study as controls. Toxicologic evaluation was performed on Wistar rats and CD1 mice by injecting high doses of OncoFAP-23 or its cold-labeled counterpart, respectively. Results: 177Lu-OncoFAP-23 emerged for its best-in-class biodistribution profile, high and prolonged tumor uptake (i.e., ∼16 percentage injected dose/g at 96 h), and low accumulation in healthy organs, which correlates well with its potent single-agent anticancer activity at low levels of administered radioactivity. Combination treatment with the tumor-targeted interleukin 2 (L19-IL2, a clinical-stage immunocytokine) further expands the therapeutic window of 177Lu-OncoFAP-23 by potentiating its in vivo antitumor activity. Proteomics studies revealed a potent tumor-directed immune response on treatment with the combination. OncoFAP-23 and natLu-OncoFAP-23 exhibited a favorable toxicologic profile, without showing any side effects or signs of toxicity. Conclusion: OncoFAP-23 presents enhanced tumor uptake and tumor retention and low accumulation in healthy organs, findings that correspond to a strongly improved in vivo antitumor efficacy. The data presented in this work support the clinical development of 177Lu-OncoFAP-23 for the treatment of FAP-positive solid tumors.
    Keywords:  OncoFAP; fibroblast activation protein; radiopharmaceutical therapeutics; radiopharmaceuticals; targeted cancer therapy; tumor microenvironment
    DOI:  https://doi.org/10.2967/jnumed.124.268200
  16. Nat Commun. 2024 Sep 09. 15(1): 7877
    Biostructural, biochemical and biophysical studies of mutant IDH1.
    Mark A McCoy, Jun Lu, F Richard Miller, Stephen M Soisson, Michael H Lam, Christian Fischer.
      We report bio-structural, bio-chemical and bio-physical evidence demonstrating how small molecules can bind to both wild-type and mutant IDH1, but only inhibit the enzymatic activity of the mutant isoform. Enabled through x-ray crystallography, we characterized a series of small molecule inhibitors that bound to mutant IDH1 differently than the marketed inhibitor Ivosidenib, for which we have determined the x-ray crystal structure. Across the industry several mutant IDH1 inhibitor chemotypes bind to this allosteric IDH1 pocket and selectively inhibit the mutant enzyme. Detailed characterization by a variety of biophysical techniques and NMR studies led us to propose how compounds binding in the allosteric IDH1 R132H pocket inhibit the production of 2-Hydroxy glutarate.
    DOI:  https://doi.org/10.1038/s41467-024-51692-0
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