Medical and Biotechnological Aspects

  • Jonathan Walton


As discussed in Chap.  2, higher fungi including mushrooms make many bioactive compounds. In this chapter we restrict our discussion to the cycloamanide family of ribosomally biosynthesized cyclic peptides found, to date, only in some species of Amanita, Lepiota, and Galerina. Information on the taxonomy, chemistry, and clinical aspects of mushroom poisonings due to non-peptidic mushroom components, including orellanine, gyromitrin, muscarine, illudin, coprine, and muscimol, are covered in Bresinky and Besl (1990), Benjamin (1995), and other books and web sites cited at the end of this chapter. Within the cycloamanide family, from the medical point of view, it is appropriate that the emphasis be exclusively on the amatoxins. Poisonings of mammals are due solely to the amatoxins because the phallotoxins are not absorbed from the digestive tracts of mammals (or, to the best of our knowledge, any other animal), and none of the monocyclic cycloamanides are known to be poisonous to mammals by any mode of ingestion.


  1. Ammirati JF, Traquair JA, Horgen PA (1985) Poisonous mushrooms of the Northern United States and Canada. University of Minnesota Press, Minneapolis, and Fitzhenry & Whiteside, Ltd., MarkhamGoogle Scholar
  2. Anderl J, Echner H, Faulstich H (2012) Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology. Beilstein J Org Chem 8:2072–2084. CrossRefPubMedPubMedCentralGoogle Scholar
  3. Anderl J, Faulstich H, Hechler T, Kulke M (2013) Antibody–drug conjugate payloads. Methods Mol Biol 1045:51–70. CrossRefPubMedGoogle Scholar
  4. Aubrey BJ, Strasser A, Kelly GL (2016) Tumor-suppressor functions of the TP53 pathway. Cold Spring Harb Perspect Med 6: pii: a026062. doi: CrossRefPubMedPubMedCentralGoogle Scholar
  5. Barak LS, Nothnagel EA, DeMarco EF, Webb WW (1981) Differential staining of actin in metaphase spindles with 7-nitrobenz-2-oxa-1,3-diazole-phallacidin and fluorescent DNase: is actin involved in chromosomal movement? Proc Natl Acad Sci U S A 78:3034–3038CrossRefGoogle Scholar
  6. Barbanti-Brodano G, Derenzini M, Fiume L (1974) Toxic action of a phalloidin-albumin conjugate on cells with a high protein uptake. Nature 248:63–64CrossRefGoogle Scholar
  7. Barber CJS, Pjuara PT, Reed DW, Chiwocha S, Zhang H, Covello PS (2013) The two-step biosynthesis of cyclic peptides from linear precursors in a member of the plant family Caryophyllaceae involves cyclization by a serine protease-like enzyme. J Biol Chem 288:12500–12510. CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bazzicalupo A, Berch S, Callan B, Ceska O, Kroeger P, Li R, McIntyre L, Miao V, Stanwick R, Trudell S, Vellinga EC, Walton JD, Arevalo W, Asay A, Auxier B, Ceska A, Dee J, Gamiet S, Landry B, Le Renard L, Schwarz C, Super L, van der Meer B, Berbee M (2018) White paper on strategies to reduce risks and expand appreciation of foraged wild mushrooms. McIlvanea 26.
  9. Beck JG, Chatterjee J, Laufer B, Kiran MU, Frank AO, Neubauer S, Ovadia O, Greenberg S, Gilon C, Hoffman A, Kessler H (2012) Intestinal permeability of cyclic peptides: common key backbone motifs identified. J Am Chem Soc 134:12125–12133. CrossRefPubMedGoogle Scholar
  10. Ben Khelil M, Zhioua M, Bakir O, Allouche M, Gloulou F, Banasr A, Haouet S, Hedhili A, Hamdoun M (2010) Intoxication mortelle par Lepiota brunnioincarnata: à propos de 4 cas. Ann Biol Clin (Paris) 68:561–567. CrossRefGoogle Scholar
  11. Benedict RG, Brady LR (1967) Further studies on fermentative production of toxic cyclopeptides by Galerina marginata (Fr Kühn). Lloydia 30:372–378Google Scholar
  12. Benedict RG, Tyler VE Jr, Brady LR, Weber LJ (1966) Fermentative production of Amanita toxins by a strain of Galerina marginata. J Bacteriol 91:1380–1381PubMedPubMedCentralGoogle Scholar
  13. Benjamin DR (1995) Mushrooms: poisons and panaceas. A handbook for naturalists, mycologists, and physicians. WH Freeman, New YorkGoogle Scholar
  14. Beug MW (2016)Amatoxinmushroom poisoning in North America 2015–2016. McIlvainea 25. Accessed Sept 2017, at
  15. Bhat A, Roberts LR, Dwyer JJ (2015) Lead discovery and optimization strategies for peptide macrocycles. Eur J Med Chem 94:471–479. CrossRefPubMedGoogle Scholar
  16. Bionda N, Fasan R (2017) Ribosomal synthesis of thioether-bridged bicyclic peptides. Methods Mol Biol 1495:57–76. CrossRefPubMedPubMedCentralGoogle Scholar
  17. Bockus AT, McEwen CM, Lokey RS (2013) Form and function in cyclic peptide natural products: a pharmacokinetic perspective. Curr Top Med Chem 13:821–836. CrossRefPubMedGoogle Scholar
  18. Bolewska-Pedyczak E, Wieczorek Z, Zimecki M, Siemion IZ (1993) Immunosuppressive activity of some peptides related to cycloamanide A (CyA A) and to the active fragment of a peptide immunomodulator from ovine colostrum. Arch Immunol Ther Exp 41:297–301Google Scholar
  19. Bradner JE (2015) An essential passenger with p53. Nature 520:626–627. CrossRefPubMedGoogle Scholar
  20. Bresinsky A, Besl H (1990) A colour atlas of poisonous fungi: a handbook for pharmacists, doctors, and biologists. Wolfe Publishing, LondonGoogle Scholar
  21. Cardote TAF, Ciulli A (2016) Cyclic and macrocyclic peptides as chemical tools to recognise protein surfaces and probe protein-protein interactions. ChemMedChem 11:787–794. CrossRefPubMedGoogle Scholar
  22. Cascales L, Henriques ST, Kerr MC, Huang YH, Sweet MJ, Daly NL, Craik DJ (2011) Identification and characterization of a new family of cell-penetrating peptides: cyclic cell-penetrating peptides. J Biol Chem 286:36932–36943. CrossRefPubMedPubMedCentralGoogle Scholar
  23. Chekan JR, Estrada P, Covello PS, Nair SK (2017) Characterization of the macrocyclase involved in the biosynthesis of RiPP cyclic peptides in plants. Proc Natl Acad Sci U S A 114:6551–6556. CrossRefPubMedPubMedCentralGoogle Scholar
  24. Chung HM, Lee MG, Dietrich P, Huang J, Van der Ploeg LH (1993) Disruption of largest subunit RNA polymerase II genes in Trypanosoma brucei. Mol Cell Biol 13:3734–3743. CrossRefPubMedPubMedCentralGoogle Scholar
  25. Clark RJ, Fischer H, Dempster L, Daly NL, Rosengren KJ, Nevin ST, Meunier FA, Adams DJ, Craik DJ (2005) Engineering stable peptide toxins by means of backbone cyclization: stabilization of the α-conotoxin MII. Proc Natl Acad Sci U S A 102:13767–13772. CrossRefGoogle Scholar
  26. Craik DJ, Mylne JS, Daly NL (2010) Cyclotides: macrocyclic peptides with applications in drug design and agriculture. Cell Mol Life Sci 67:9–16. CrossRefGoogle Scholar
  27. Czekster CM, Naismith JH (2017) Kinetic landscape of a peptide bond-forming prolyl oligopeptidase. Biochemistry 56:2086–2095. CrossRefPubMedPubMedCentralGoogle Scholar
  28. Czekster CM, Ludewig H, McMahon SA, Naismith JH (2017) Characterization of a dual function macrocyclase enables design and use of efficient macrocyclization substrates. Nat Commun 8:1045. CrossRefPubMedPubMedCentralGoogle Scholar
  29. Davis MT, Preston JF 3rd (1981) A conjugate of α-amanitin and monoclonal immunoglobulin G to Thy 1.2 antigen is selectively toxic to T lymphoma cells. Science 213:1385–1388. CrossRefGoogle Scholar
  30. Davis-Searles PR, Nakanishi Y, Kim NC, Graf TN, Oberlies NH, Wani MC, Wall ME, Agarwal R, Kroll DJ (2005) Milk thistle and prostate cancer: differential effects of pure flavonolignans from Silybum marianum on antiproliferative end points in human prostate carcinoma cells. Cancer Res 65:4448–4457. CrossRefPubMedGoogle Scholar
  31. Dougherty PG, Qian Z, Pei D (2017) Macrocycles as protein-protein interaction inhibitors. Biochem J 474:1109–1125. CrossRefPubMedGoogle Scholar
  32. Enjalbert F, Rapior S, Nouguier-Soulé J, Guillon S, Amouroux N, Cabot C (2002) Treatment of amatoxin poisoning: 20-year retrospective analysis. J Toxicol Clin Toxicol 40:715–757CrossRefGoogle Scholar
  33. Epis S, Matinato C, Gentili G, Varotto F, Bandi C, Sassera D (2010) Molecular detection of poisonous mushrooms in different matrices. Mycologia 102:747–754. CrossRefPubMedGoogle Scholar
  34. Faulstich H, Fiume L (1985) Protein conjugates of fungal toxins. Methods Enzymol 112:225–237CrossRefGoogle Scholar
  35. Filigenzi MS, Poppenga RH, Tiwary AK, Puschner B (2007) Determination of α-amanitin in serum and liver by multistage linear ion trap mass spectrometry. J Agric Food Chem 55:2784–2790. CrossRefPubMedGoogle Scholar
  36. Fiume L, Derenzini M, Marinozzi V, Petazzi F, Testoni A (1973) Pathogenesis of gastro-intestinal symptomatology during poisoning by Amanita phalloides. Experientia 29:1520–1521CrossRefGoogle Scholar
  37. Floersheim GL, Eberhard M, Tschumi P, Duckert F (1978) Effects of penicillin and silymarin on liver enzymes and blood clotting factors in dogs given a boiled preparation of Amanita phalloides. Toxicol Appl Pharmacol 46:455–462CrossRefGoogle Scholar
  38. Frank IC, Cummins L (1987) Amanita poisoning treated with endoscopic biliary diversion. J Emerg Nurs 13:132–136PubMedGoogle Scholar
  39. Garcia J, Costa VM, Carvalho A, Baptista P, de Pinho PG, de Lourdes BM, Carvalho F (2015) Amanita phalloides poisoning: mechanisms of toxicity and treatment. Food Chem Toxicol 86:41–55. CrossRefPubMedGoogle Scholar
  40. Gausterer C, Penker M, Krisai-Greilhuber I, Stein C, Stimpfl T (2014) Rapid genetic detection of ingested Amanita phalloides. Forensic Sci Int Genet 9:66–71. CrossRefPubMedGoogle Scholar
  41. Gicquel T, Lepage S, Fradin M, Tribut O, Duretz B, Morel I (2014) Amatoxins (α- and β-amanitin) and phallotoxin (phalloidin) analyses in urines using high-resolution accurate mass LC-MS technology. J Anal Toxicol 38:335–340. CrossRefPubMedPubMedCentralGoogle Scholar
  42. Göransson U, Burman R, Gunasekera S, Strömstedt AA, Rosengren KJ (2012) Circular proteins from plants and fungi. J Biol Chem 287:27001–27006. CrossRefPubMedPubMedCentralGoogle Scholar
  43. Grabhorn E, Nielsen D, Hillebrand G, Brinkert F, Herden U, Fischer L, Ganschow R (2013) Successful outcome of severe Amanita phalloides poisoning in children. Pediatr Transplant 17:550–555. CrossRefPubMedGoogle Scholar
  44. Haefelé C, Bonfils C, Sauvaire Y (1997) Characterization of a dioxygenase from Trigonella foenum-graecum involved in 4-hydroxyisoleucine biosynthesis. Phytochemistry 44:563–566CrossRefGoogle Scholar
  45. Hallen HE, Luo H, Scott-Craig JS, Walton JD (2007) Gene family encoding the major toxins of lethal Amanita mushrooms. Proc Natl Acad Sci U S A 104:19097–19101. CrossRefPubMedPubMedCentralGoogle Scholar
  46. Harper KA, Smart CD, Davis RM (2011) Development of a DNA-based macroarray for the detection and identification of Amanita species. J Forensic Sci 56:1003–1009. CrossRefPubMedGoogle Scholar
  47. Hechler T, Kulke M, Müller C, Pahl A, Anderl J (2014) Amanitin-based antibody-drug conjugates targeting the prostate-specific membrane antigen. In: Proceedings of the 105th annual meeting of the American Association for Cancer Research. Cancer Res 74 (19 Suppl): Abstract 664. doi: CrossRefGoogle Scholar
  48. Heinis C (2014) Tools and rules for macrocycles. Nat Chem Biol 10:696–698. CrossRefPubMedGoogle Scholar
  49. Hetrick KJ, van der Donk WA (2017) Ribosomally synthesized and post-translationally modified peptide natural product discovery in the genomic era. Curr Opin Chem Biol 38:36–44. CrossRefPubMedGoogle Scholar
  50. Hewitt WM, Leung SS, Pye CR, Ponkey AR, Bednarek M, Jacobson MP, Lokey RS (2015) Cell-permeable cyclic peptides from synthetic libraries inspired by natural products. J Am Chem Soc 137:715–721. CrossRefPubMedGoogle Scholar
  51. Jaeger A, Jehl F, Flesch F, Sauder P, Kopferschmitt J (1993) Kinetics of amatoxins in human poisoning: therapeutic implications. J Toxicol Clin Toxicol 31:63–80CrossRefGoogle Scholar
  52. Jagadish K, Gould A, Borra R, Majumder S, Mushtaq Z, Shekhtman A, Camarero JA (2015) Recombinant expression and phenotypic screening of a bioactive cyclotide against α-synuclein-induced cytotoxicity in baker’s yeast. Angew Chem Int Ed Eng 54:8390–8394. CrossRefGoogle Scholar
  53. Javed S, Kohli K, Ali M (2011) Reassessing bioavailability of silymarin. Altern Med Rev 16:239–249PubMedGoogle Scholar
  54. Jetté L, Harvey L, Eugeni K, Levens N (2009) 4-Hydroxyisoleucine: a plant-derived treatment for metabolic syndrome. Curr Opin Investig Drugs 10:353–358Google Scholar
  55. Ji Y, Majumder S, Millard M, Borra R, Bi T, Elnagar AY, Neamati N, Shekhtman A, Camarero JA (2013) In vivo activation of the p53 tumor suppressor pathway by an engineered cyclotide. J Am Chem Soc 135:11623–11633. CrossRefPubMedPubMedCentralGoogle Scholar
  56. Kadam RU, Juraszek J, Brandenburg B, Buyck C, Schepens WBG, Kesteleyn B, Stoops B, Vreeken RJ, Vermond J, Goutier W, Tang C, Vogels R, Friesen RHE, Goudsmit J, van Dongen MJP, Wilson IA (2017) Potent peptidic fusion inhibitors of influenza virus. Science 358:496–502. CrossRefGoogle Scholar
  57. Kaneko H, Tomomasa T, Inoue Y, Kunimoto F, Fukusato T, Muraoka S, Gonmori K, Matsumoto T, Morikawa A (2001) Amatoxin poisoning from ingestion of Japanese Galerina mushrooms. J Toxicol Clin Toxicol 39:413–416CrossRefGoogle Scholar
  58. Kaya E, Surmen MG, Yaykasli KO, Karahan S, Oktay M, Turan H, Colakoglu S, Erdem H (2014) Dermal absorption and toxicity of alpha amanitin in mice. Cutan Ocul Toxicol 33:154–160. CrossRefGoogle Scholar
  59. Kling A, Lukat P, Almeida DV, Bauer A, Fontaine E, Sordello S, Zaburannyi N, Herrmann J, Wenzel SC, König C, Ammerman NC, Barrio MB, Borchers K, Bordon-Pallier F, Brönstrup M, Courtemanche G, Gerlitz M, Geslin M, Hammann P, Heinz DW, Hoffmann H, Klieber S, Kohlmann M, Kurz M, Lair C, Matter H, Nuermberger E, Tyagi S, Fraisse L, Grosset JH, Lagrange S, Müller R (2015) Targeting DnaN for tuberculosis therapy using novel griselimycins. Science 348:1106–1112. CrossRefPubMedGoogle Scholar
  60. Kooter JM, Borst P (1984) Alpha-amanitin-insensitive transcription of variant surface glycoprotein genes provides further evidence for discontinuous transcription in trypanosomes. Nucleic Acids Res 12:9457–9472CrossRefGoogle Scholar
  61. Kries H (2016) Biosynthetic engineering of nonribosomal peptide synthetases. J Pept Sci 22:564–570. CrossRefPubMedGoogle Scholar
  62. Kritzer JA, Hamamichi S, McCaffery JM, Santagata S, Naumann TA, Caldwell KA, Caldwell GA, Lindquist S (2009) Rapid selection of cyclic peptides that reduce α-synuclein toxicity in yeast and animal models. Nat Chem Biol 5:655–663. CrossRefGoogle Scholar
  63. Lacombe G, St-Onge M (2016) Towards evidence-based emergency medicine: best BETs from the Manchester royal infirmary. BET 1: silibinin in suspected amatoxin-containing mushroom poisoning. Emerg Med J 33:76–77. CrossRefPubMedGoogle Scholar
  64. Letschert K, Faulstich H, Keller D, Keppler D (2006) Molecular characterization and inhibition of amanitin uptake into human hepatocytes. Toxicol Sci 91:140–149. CrossRefPubMedPubMedCentralGoogle Scholar
  65. Li P, Deng W, Li T (2014) The molecular diversity of toxin gene families in lethal Amanita mushrooms. Toxicon 83:59–68. CrossRefPubMedPubMedCentralGoogle Scholar
  66. Lian W, Upadhyaya P, Rhodes CA, Liu Y, Pei D (2013) Screening bicyclic peptide libraries for protein–protein interaction inhibitors: discovery of a tumor necrosis factor-α antagonist. J Am Chem Soc 135:11990–11995. CrossRefPubMedGoogle Scholar
  67. Lincoff G, Mitchel DH (1977) Toxic and hallucinogenic mushroom poisoning: a handbook for physicians and mushroom hunters. Van Nostrand Reinhold, New YorkGoogle Scholar
  68. Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, Jiang D, Rodriguez-Aguayo C, Lopez-Berestein G, Rao PH, Maru DM, Pahl A, He X, Sood AK, Ellis LM, Anderl J, Lu X (2015a) TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature 520:697–701. CrossRefPubMedPubMedCentralGoogle Scholar
  69. Liu Y, Wang L, Lu X (2015b) A new way to target p53-defective colorectal cancer. Future Oncol 11:3101–3104. CrossRefPubMedGoogle Scholar
  70. Luo H, Hallen-Adams HE, Scott-Craig JS, Walton JD (2012) Ribosomal biosynthesis of α-amanitin in Galerina marginata. Fungal Genet Biol 49:123–129. CrossRefPubMedPubMedCentralGoogle Scholar
  71. Luo H, Hong SY, Sgambelluri RM, Angelos E, Li X, Walton JD (2014) Peptide macrocyclization catalyzed by a prolyl oligopeptidase involved in α-amanitin biosynthesis. Chem Biol 21:1610–1617. CrossRefPubMedPubMedCentralGoogle Scholar
  72. Luo H, DuBois B, Sgambelluri RM, Angelos ER, Li X, Holmes D, Walton JD (2015) Production of 15N-labeled α-amanitin in Galerina marginata. Toxicon 103:60–64. CrossRefPubMedPubMedCentralGoogle Scholar
  73. Maeta K, Ochi T, Tokimoto K, Shimomura N, Maekawa N, Kawaguchi N, Nakaya M, Kitamoto Y, Aimi T (2008) Rapid species identification of cooked poisonous mushrooms by using real time PCR. Appl Environ Microbiol 74:3306–3309. CrossRefPubMedPubMedCentralGoogle Scholar
  74. Matinkhoo K, Pryyma A, Todorovic M, Patrick BO, Perrin DM (2018) Synthesis of the death cap mushroom toxin α-amanitin. J Am Chem Soc, in press.
  75. Meier-Abt F, Faulstich H, Hagenbuch B (2004) Identification of phalloidin uptake systems of rat and human liver. Biochim Biophys Acta 1664:64–69. CrossRefGoogle Scholar
  76. Mengs U, Pohl RT, Mitchell T (2012) Legalon® SIL: the antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning. Curr Pharm Biotechnol 13:1964–1970. Scholar
  77. Miranda E, Nordgren IK, Male AL, Lawrence CE, Hoakwie F, Cuda F, Court W, Fox KR, Townsend PA, Packham GK, Eccles SA, Tavassoli A (2013) A cyclic peptide inhibitor of HIF-1 heterodimerization that inhibits hypoxia signaling in cancer cells. J Am Chem Soc 135:10418–10425. CrossRefPubMedPubMedCentralGoogle Scholar
  78. Mitchell ST, Olson KR (2008) Intravenous silibinin in the management of amatoxin poisoning: first usage in an American cohort. Clin Toxicol 46:396. (Abstract)Google Scholar
  79. Moldenhauer G, Salnikov AV, Lüttgau S, Herr I, Anderl J, Faulstich H (2012) Therapeutic potential of amanitin-conjugated anti-epithelial cell adhesion molecule monoclonal antibody against pancreatic carcinoma. J Natl Cancer Inst 104:622–634. CrossRefPubMedGoogle Scholar
  80. Mootz HD (ed) (2017) Split inteins: methods and protocols, Meth Mol Biol, vol 1495. Springer, New York. CrossRefGoogle Scholar
  81. Mottram AR, Lazio MP, Bryant SM (2010) Lepiota subincarnata J.E. Lange induced fulminant hepatic failure presenting with pancreatitis. J Med Toxicol 6:155–157. CrossRefPubMedPubMedCentralGoogle Scholar
  82. Mühlbach HP, Sänger HL (1979) Viroid replication is inhibited by alpha-amanitin. Nature 278:185–188CrossRefGoogle Scholar
  83. Muszyńska K, Ostrowska D, Bartnicki F, Kowalska E, Bodaszewska-Lubaś M, Hermanowicz P, Faulstich H, Strzałka W (2017) Selection and analysis of a DNA aptamer binding α-amanitin from Amanita phalloides. Acta Biochim Pol 64:401–406. CrossRefPubMedGoogle Scholar
  84. Nguyen GK, Wang S, Qiu Y, Hemu X, Lian Y, Tam JP (2014) Butelase 1 is an Asx-specific ligase enabling peptide macrocyclization and synthesis. Nat Chem Biol 10:732–738. CrossRefGoogle Scholar
  85. Nguyen GK, Kam A, Loo S, Jansson AE, Pan LX, Tam JP (2015) Butelase 1: a versatile ligase for peptide and protein macrocyclization. J Am Chem Soc 137:15398–15401. CrossRefGoogle Scholar
  86. Nguyen GK, Hemu X, Quek JP, Tam JP (2016) Butelase-mediated macrocyclization of D-amino-acid-containing peptides. Angew Chem Int Ed Eng 55:12802–12806. CrossRefGoogle Scholar
  87. Niedermeyer TH, Daily A, Swiatecka-Hagenbruch M, Moscow JA (2014) Selectivity and potency of microcystin congeners against OATP1B1 and OATP1B3 expressing cancer cells. PLoS One 10:e91476. CrossRefGoogle Scholar
  88. Olson KR, Pond SM, Seward J, Healey K, Woo OF, Becker CE (1982) Amanita phalloides-type mushroom poisoning. West J Med 137:282–289PubMedPubMedCentralGoogle Scholar
  89. Pálfi A, Hechler T, Müller C, Pahl A, Kulke M (2016) CD269 – a promising target for amanitin based ADCs. In: Proceedings of the 107th annual meeting of the American Association for Cancer Research. Cancer Res 76 (14 Suppl): Abstract 2973. doi: CrossRefGoogle Scholar
  90. Parmley S (2014) Resurrecting a magic bullet. SciBX 7.
  91. Pulman JA, Childs KL, Sgambelluri RM, Walton JD (2016) Expansion and diversification of the MSDIN family of cyclic peptide genes in the poisonous agarics Amanita phalloides and A. bisporigera. BMC Genomics 17:1038. CrossRefPubMedPubMedCentralGoogle Scholar
  92. Quartararo JS, Wu P, Kritzer JA (2017) Peptide bicycles that inhibit the Grb2 SH2 domain. Chembiochem 13:1490–1496. CrossRefGoogle Scholar
  93. Rhodes CA, Pei D (2017) Bicyclic peptides as next-generation therapeutics. Chemistry 23:12690–12703. CrossRefPubMedGoogle Scholar
  94. Robinson-Fuentes VA, Jaime-Sánchez JL, García-Aguilar L, Gómez-Peralta M, Vázquez-Garcidueñas MS, Vázquez-Marrufo G (2008) Determination of α- and β-amanitin in clinical urine samples by capillary zone electrophoresis. J Pharm Biomed Anal 47:913–917. CrossRefGoogle Scholar
  95. Sable R, Durek T, Taneja V, Craik DJ, Pallerla S, Gauthier T, Jois S (2016) Constrained cyclic peptides as immunomodulatory inhibitors of the CD2:CD58 protein-protein interaction. ACS Chem Biol 11:2366–2374. CrossRefPubMedPubMedCentralGoogle Scholar
  96. Santi L, Maggioli C, Mastroroberto M, Tufoni M, Napoli L, Caraceni (2012) Acute liver failure caused by Amanita phalloides poisoning. Int J Hepatol 2012:487480. CrossRefGoogle Scholar
  97. Sgambelluri RM, Epis S, Sassera D, Luo H, Angelos ER, Walton JD (2014) Profiling of amatoxins and phallotoxins in the genus Lepiota by liquid chromatography combined with UV absorbance and mass spectrometry. Toxins 6:2336–2347. doi: 10.3390/toxins6082336CrossRefPubMedPubMedCentralGoogle Scholar
  98. Sgambelluri RM, Smith MO, Walton JD (2018) Versatility of prolyl oligopeptidase B in peptide macrocyclization. ACS Synth Biol 7:145–152. CrossRefPubMedPubMedCentralGoogle Scholar
  99. Sievers EL, Senter PD (2013) Antibody-drug conjugates in cancer therapy. Annu Rev Med 64:15–29. CrossRefPubMedGoogle Scholar
  100. Smith MR, Davis RL (2016) Mycetismus: a review. Gastroenterol Rep 4:107–112. CrossRefGoogle Scholar
  101. Smith JM, Frost JR, Fasan R (2013) Design, synthesis, and diversification of ribosomally derived peptide macrocycles. Curr Opin Struct Biol 23:571–580. CrossRefPubMedGoogle Scholar
  102. Spoerke DG, Rumack BH (eds) (1994) Handbook of mushroom poisoning: diagnosis and treatment. CRC Press, Boca RatonGoogle Scholar
  103. Tang S, Zhou Q, He Z, Luo T, Zhang P, Cai Q, Yang Z, Chen J, Chen Z (2016) Cyclopeptide toxins of lethal amanitas: compositions, distribution and phylogenetic implication. Toxicon 120:78–88. CrossRefPubMedPubMedCentralGoogle Scholar
  104. Tavassoli A (2017) SICLOPPS cyclic peptide libraries in drug discovery. Curr Opin Chem Biol 38:30–35. CrossRefPubMedGoogle Scholar
  105. Teicher BA (2014) Antibody drug conjugates. Curr Opin Oncol 26:476–483. CrossRefPubMedGoogle Scholar
  106. Theologis A, Huynh TV, Davis RW (1985) Rapid induction of specific mRNAs by auxin in pea epicotyl tissue. J Mol Biol 183:53–68CrossRefGoogle Scholar
  107. Tomková J, Ondra P, Válka I (2015) Simultaneous determination of mushroom toxins α-amanitin, β-amanitin and muscarine in human urine by solid-phase extraction and ultra-high-performance liquid chromatography coupled with ultra-high-resolution TOF mass spectrometry. Forensic Sci Int 251:209–213. CrossRefPubMedPubMedCentralGoogle Scholar
  108. Truman AW (2016) Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides. Beilstein J Org Chem 12:1250–1268. CrossRefPubMedPubMedCentralGoogle Scholar
  109. Udugamasooriya DG, Spaller MR (2008) Conformational constraint in protein ligand design and the inconsistency of binding entropy. Biopolymers 89:653–667. CrossRefPubMedGoogle Scholar
  110. Upadhyaya P, Qian Z, Selner NG, Clippinger SR, Wu Z, Briesewitz R, Pei D (2015) Inhibition of Ras signaling by blocking Ras–effector interactions with cyclic peptides. Angew Chem Int Ed 54:7602–7606. CrossRefGoogle Scholar
  111. Varvenne D, Retornaz K, Metge P, De Haro L, Minodier P (2015) Amatoxin-containing mushroom (Lepiota brunneoincarnata) familial poisoning. Pediatr Emerg Care 31:277–288. CrossRefPubMedPubMedCentralGoogle Scholar
  112. Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD (2002) Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem 45:265–2623. On-line analysis at CrossRefGoogle Scholar
  113. Vo KT, Montgomery ME, Mitchell ST, Scheerlinck PH, Colby DK, Meier KH, Kim-Katz S, Anderson IB, Offerman SR, Olson KR, Smollin CG (2017) Amanita phalloides mushroom poisonings – Northern California, December 2016. MMWR Morb Mortal Wkly Rep 66:549–553. https://doi/org/10.15585/mmwr.mm6621a1CrossRefGoogle Scholar
  114. Vogel G, Tuchweber B, Trost W, Mengs U (1984) Protection by silibinin against Amanita phalloides intoxication in beagles. Toxicol Appl Pharmacol 73:355–362CrossRefGoogle Scholar
  115. Wang CK, Craik DJ (2016) Cyclic peptide oral bioavailability: lessons from the past. Biopolymers 106:901–909. CrossRefPubMedGoogle Scholar
  116. Wang M, Xie T, Chang Z, Wang L, Xie X, Kou Y, Xu H, Gao X (2015) A new type of liquid silymarin proliposome containing bile salts: its preparation and improved hepatoprotective effects. PLoS One 10:e0143625. CrossRefPubMedPubMedCentralGoogle Scholar
  117. Ward J, Kapadia K, Brush E, Salhanick SD (2013) Amatoxin poisoning: case reports and review of current therapies. J Emerg Med 44:116–121. CrossRefPubMedGoogle Scholar
  118. Weidmann J, Craik DJ (2016) Discovery, structure, function, and applications of cyclotides: circular proteins from plants. J Exp Bot 67:4801–4812. CrossRefPubMedGoogle Scholar
  119. White AM, Craik DJ (2016) Discovery and optimization of peptide macrocycles. Expert Opin Drug Discovery 11:1151–1163. CrossRefGoogle Scholar
  120. Wieczorek Z, Siemion IZ, Zimecki M, Bolewska-Pedyczak E, Wieland T (1993) Immunosuppressive activity in the series of cycloamanide peptides from mushrooms. Peptides 14:1–5CrossRefGoogle Scholar
  121. Wieland T (1986) Peptides of poisonous Amanita mushrooms. Springer, New YorkCrossRefGoogle Scholar
  122. Wieland T, Wieland O (1972) The toxic peptides of Amanita species. In: Kadis S, Ciegler A, Ajl SJ (eds) Microbial toxins, vol 8. Academic, New York, pp 249–280Google Scholar
  123. Wołoszyn A, Kotłowski R (2017) A universal method for the identification of genes encoding amatoxins and phallotoxins in poisonous mushrooms. Rocz Panstw Zakl Hig 68:247–251PubMedGoogle Scholar
  124. Zafar MI, Gao F (2016) 4-Hydroxyisoleucine: a potential new treatment for type 2 diabetes mellitus. BioDrugs 30:255–262. CrossRefPubMedGoogle Scholar
  125. Zhang P, Chen Z, Hu J, Wei B, Zhang Z, Hu W (2005) Production and characterization of amanitin toxins from a pure culture of Amanita exitialis. FEMS Microbiol Lett 252:223–228. CrossRefGoogle Scholar
  126. Zipperer A, Konnerth MC, Laux C, Berscheid A, Janek D, Weidenmaier C, Burian M, Schilling NA, Slavetinsky C, Marschal M, Willmann M, Kalbacher H, Schittek B, Brötz-Oesterhelt H, Grond S, Peschel A, Krismer B (2016) Human commensals producing a novel antibiotic impair pathogen colonization. Nature 535:511–516. CrossRefPubMedGoogle Scholar
  127. Zorzi A, Deyle K, Heinis C (2017) Cyclic peptide therapeutics: past, present, and future. Curr Opin Chem Biol 38:24–29. Scholar
  128. Zuliani AM, Kabar I, Mitchell T, Heinzow HS (2016) Akutes Leberversagen nach Knollenblätterpilz-Ingestion. Dtsch Med Wochenschr 141:940–942. CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Jonathan Walton
    • 1
  1. 1.United States Department of Energy Plant Research Lab and Department of Plant BiologyMichigan State UniversityEast LansingUSA

Personalised recommendations