Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

  1. Sebastian Günther
  2. Patrick Y. A. Reinke
  3. Dominik Oberthuer
  4. Oleksandr Yefanov
  5. Helen Ginn
  6. Susanne Meier
  7. Thomas J. Lane
  8. Kristina Lorenzen
  9. Luca Gelisio
  10. Wolfgang Brehm
  11. Illona Dunkel
  12. Martin Domaracky
  13. Sofiane Saouane
  14. Julia Lieske
  15. Christiane Ehrt
  16. Faisal Koua
  17. Alexandra Tolstikova
  18. Thomas A. White
  19. Michael Groessler
  20. Holger Fleckenstein
  21. Fabian Trost
  22. Marina Galchenkova
  23. Yaroslav Gevorkov
  24. Chufeng Li
  25. Salah Awel
  26. Ariana Peck
  27. P. Lourdu Xavier
  28. Miriam Barthelmess
  29. Frank Schlünzen
  30. Nadine Werner
  31. Hina Andaleeb
  32. Najeeb Ullah
  33. Sven Falke
  34. Bruno Alves Franca
  35. Martin Schwinzer
  36. Hévila Brognaro
  37. Brandon Seychell
  38. Henry Gieseler
  39. Diogo Melo
  40. Joanna I. Zaitseva-Kinneberg
  41. Brenna Norton-Baker
  42. Juraj Knoska
  43. Gisel Esperanza
  44. Aida Rahmani Mashhour
  45. Filip Guicking
  46. Vincent Hennicke
  47. Pontus Fischer
  48. Cromarte Rogers
  49. Diana C. F. Monteiro
  50. Johanna Hakanpää
  51. Jan Meyer
  52. Heshmat Noei
  53. Phil Gribbon
  54. Bernhard Ellinger
  55. Maria Kuzikov
  56. Markus Wolf
  57. Linlin Zhang
  58. Xinyuanyuan Sun
  59. Jonathan Pletzer-Zelgert
  60. Jan Wollenhaupt
  61. Christian Feiler
  62. Manfred Weiss
  63. Eike-Christian Schulz
  64. Pedram Mehrabi
  65. Christina Schmidt
  66. Robin Schubert
  67. Huijong Han
  68. Boris Krichel
  69. Yaiza Fernández-García
  70. Beatriz Escudero-Pérez
  71. Stephan Günther
  72. Dusan Turk
  73. Charlotte Uetrecht
  74. Tobias Beck
  75. Henning Tidow
  76. Ashwin Chari
  77. Andrea Zaliani
  78. Matthias Rarey
  79. Russell Cox
  80. Rolf Hilgenfeld
  81. Henry N. Chapman
  82. Arwen R. Pearson
  83. Christian Betzel
  84. Alke Meents
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Abstract

Here we present the crystal structure of SARS-CoV-2 main protease (M pro ) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of M pro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of M pro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by M pro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by M pro , followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors.

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