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BC-007

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BC-007
Drawing of the structure of a molecule of BC-007
Clinical data
Other names
  • ARC183, ARC-183
  • BC007, BC-007
  • GS522, GS-522
  • G15D
  • HD1
  • HTQ
  • TBA
  • d(GGTTGGTGTGGTTGG)
  • 5'-GGTTGGTGTGGTTGG-3'
Routes of
administration		Infusion
Pharmacokinetic data
Elimination half-life2.9-11 min
Identifiers
  • [(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-[[[(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-2-(hydroxymethyl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-3-yl]oxy-hydroxyphosphoryl]oxymethyl]oxolan-3-yl] [(2R,3S,5R)-5-(2-amino-6-oxo-1H-purin-9-yl)-3-phosphonooxyoxolan-2-yl]methyl hydrogen phosphate
CAS Number
PubChem CID
PubChem SID
DrugBank
ChEBI
Chemical and physical data
FormulaC150H188N57O97P15
Molar mass4806.07 g·mol−1
3D model (JSmol)
  • OC[C@H]1O[C@@H](N2C=3N=C(NC(C3N=C2)=O)N)C[C@@H]1OP(OC[C@H]4O[C@@H](N5C=6N=C(NC(C6N=C5)=O)N)C[C@@H]4OP(OC[C@H]7O[C@@H](N8C=C(C(NC8=O)=O)C)C[C@@H]7OP(OC[C@H]9O[C@@H](N%10C=C(C(NC%10=O)=O)C)C[C@@H]9OP(OC[C@H]%11O[C@@H](N%12C=%13N=C(NC(C%13N=C%12)=O)N)C[C@@H]%11OP(OC[C@H]%14O[C@@H](N%15C=%16N=C(NC(C%16N=C%15)=O)N)C[C@@H]%14OP(OC[C@H]%17O[C@@H](N%18C=C(C(NC%18=O)=O)C)C[C@@H]%17OP(OC[C@H]%19O[C@@H](N%20C=%21N=C(NC(C%21N=C%20)=O)N)C[C@@H]%19OP(OC[C@H]%22O[C@@H](N%23C=C(C(NC%23=O)=O)C)C[C@@H]%22OP(OC[C@H]%24O[C@@H](N%25C=%26N=C(NC(C%26N=C%25)=O)N)C[C@@H]%24OP(OC[C@H]%27O[C@@H](N%28C=%29N=C(NC(C%29N=C%28)=O)N)C[C@@H]%27OP(OC[C@H]%30O[C@@H](N%31C=C(C(NC%31=O)=O)C)C[C@@H]%30OP(OC[C@H]%32O[C@@H](N%33C=C(C(NC%33=O)=O)C)C[C@@H]%32OP(OC[C@H]%34O[C@@H](N%35C=%36N=C(NC(C%36N=C%35)=O)N)C[C@@H]%34OP(OC[C@H]%37O[C@@H](N%38C=%39N=C(NC(C%39N=C%38)=O)N)C[C@@H]%37OP(O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O)(=O)O
  • InChI=InChI=1S/C150H188N57O97P15/c1-52-22-193(145(224)187-121(52)209)88-9-60(77(278-88)32-265-314(249,250)299-66-15-96(201-45-162-105-114(201)171-138(153)180-129(105)217)283-81(66)36-262-306(233,234)291-58-7-94(275-73(58)28-208)199-43-160-103-112(199)169-136(151)178-127(103)215)292-308(237,238)264-31-76-63(12-91(277-76)196-25-55(4)124(212)190-148(196)227)295-311(243,244)271-39-84-71(20-101(286-84)206-50-167-110-119(206)176-143(158)185-134(110)222)303-318(257,258)274-42-87-70(19-100(289-87)205-49-166-109-118(205)175-142(157)184-133(109)221)302-317(255,256)268-35-80-64(13-92(281-80)197-26-56(5)125(213)191-149(197)228)296-312(245,246)270-38-83-68(17-98(285-83)203-47-164-107-116(203)173-140(155)182-131(107)219)300-315(251,252)267-34-79-65(14-93(280-79)198-27-57(6)126(214)192-150(198)229)297-313(247,248)272-40-85-72(21-102(287-85)207-51-168-111-120(207)177-144(159)186-135(111)223)304-319(259,260)273-41-86-69(18-99(288-86)204-48-165-108-117(204)174-141(156)183-132(108)220)301-316(253,254)266-33-78-61(10-89(279-78)194-23-53(2)122(210)188-146(194)225)293-309(239,240)263-30-75-62(11-90(276-75)195-24-54(3)123(211)189-147(195)226)294-310(241,242)269-37-82-67(16-97(284-82)202-46-163-106-115(202)172-139(154)181-130(106)218)298-307(235,236)261-29-74-59(290-305(230,231)232)8-95(282-74)200-44-161-104-113(200)170-137(152)179-128(104)216/h22-27,43-51,58-102,208H,7-21,28-42H2,1-6H3,(H,233,234)(H,235,236)(H,237,238)(H,239,240)(H,241,242)(H,243,244)(H,245,246)(H,247,248)(H,249,250)(H,251,252)(H,253,254)(H,255,256)(H,257,258)(H,259,260)(H,187,209,224)(H,188,210,225)(H,189,211,226)(H,190,212,227)(H,191,213,228)(H,192,214,229)(H2,230,231,232)(H3,151,169,178,215)(H3,152,170,179,216)(H3,153,171,180,217)(H3,154,172,181,218)(H3,155,173,182,219)(H3,156,174,183,220)(H3,157,175,184,221)(H3,158,176,185,222)(H3,159,177,186,223)/t58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,71-,72-,73+,74+,75+,76+,77+,78+,79+,80+,81+,82+,83+,84+,85+,86+,87+,88+,89+,90+,91+,92+,93+,94+,95+,96+,97+,98+,99+,100+,101+,102+/m0/s1"CHEBI:140487 - 5'-GGTTGGTGTGGTTGG-3'". ChEBI. European Bioinformatics Institute. 2018-04-11. Retrieved 2023-05-31.
  • Key:LADFAOKPINUFBB-TWPNXFTKSA-N

BC-007 is an oligonucleotide aptamer, a synthetic DNA compound designed to bind other chemicals. BC-007 is in early-stage clinical trials as a lead compound intended for the potential treatment of heart failure and long COVID. In the 1990s, the substance was originally investigated as a thrombin binding aptamer or thrombin inhibitor under the name GS522 and ARC183, respectively.

Properties

BC-007 is a single-stranded DNA oligonucleotide aptamer with the nucleotide sequence 5'-GGT TGG TGT GGT TGG-3'. The proposed mechanism of action is by blocking G protein-coupled receptor autoantibodies (GPCR-AABs), which may impair heart function.[1][2][3] In preliminary human studies, it was given by infusion and had a short half-life of around 2.9 to 11 minutes.[4]

History and discovery

In 1992, Gilead Sciences applied for a process patent to manufacture aptamers that bind specific serum proteins, such as thrombin and factor X, eicosanoids, kinins (such as bradykinin), and cell surface ligands.[5] In this and other patents, as well as in research publications,[6][7][8] the process and the synthesized nucleotide sequence GGT TGG TGT GGT TGG were discussed as a direct thrombin inhibitor. In 1995, laboratory studies of the thrombin inhibitor were published under the previous name GS-522.[9][10]

Since the 1990s, GPCR autoantibodies were investigated as possible factors in the pathology of several diseases, including heart disease.[11][12][13][14][15] In parallel, treatment strategies to remove GPCR-AABs were investigated, initially using proteins or peptides to bind the antibodies.[16][17]

In 2013, scientists from the Max Delbrück Center and the Charité Heart Center reported using aptamers as a treatment for dilated cardiomyopathy in patients positive for beta-1 adrenergic receptor AABs.[18][19] In 2015-16, scientists reported that two aptamers may bind GPCR-AABs, possibly resulting in an inhibition of GPCR-AABs.[20][21]

In 2014, the biotechnology company Berlin Cures GmbH was founded to investigate the aptamer with the nucleotide sequence GGT TGG TGT GGT TGG (ARC183) under the name BC-007.[22]

Research

Heart failure

In 2018, a Phase I clinical trial found that BC-007 was well-tolerated, with no serious adverse events reported.[1][23] As of 2020, aptamers like BC-007 were being evaluated in several early-stage clinical trials for their potential safety and efficacy in treating heart failure.[24]

Long COVID

Aptamers are under invesigation as possible agents for treating various viral infections, such as COVID-19.[25][26][27] BC-007 is among several drug candidates being investigated to possibly treat the multiple disorders of long COVID.[28]

References

  1. ^ a b Düngen HD, Dordevic A, Felix SB, et al. (January 2020). "β1-Adrenoreceptor Autoantibodies in Heart Failure: Physiology and Therapeutic Implications". Circulation: Heart Failure. 13 (1): e006155. doi:10.1161/CIRCHEARTFAILURE.119.006155. PMID 31957469. S2CID 210831160.
  2. ^ Werner S, Wallukat G, Becker NP, et al. (June 2020). "The aptamer BC 007 for treatment of dilated cardiomyopathy: evaluation in Doberman Pinschers of efficacy and outcomes". ESC Heart Failure. 7 (3): 844–855. doi:10.1002/ehf2.12628. PMC 7261533. PMID 32212256.
  3. ^ Kolter, Thomas (2023). "BC-007". In Böckler, F.; Dill, B.; Eisenbrand, G.; et al. (eds.). Römpp [Online] (in German). Stuttgart: Georg Thieme Verlag.
  4. ^ Becker NP, Haberland A, Wenzel K, et al. (May 2020). "A Three-Part, Randomised Study to Investigate the Safety, Tolerability, Pharmacokinetics and Mode of Action of BC 007, Neutraliser of Pathogenic Autoantibodies Against G-Protein Coupled Receptors in Healthy, Young and Elderly Subjects". Clinical Drug Investigation. 40 (5): 433–447. doi:10.1007/s40261-020-00903-9. PMC 7181550. PMID 32222912.
  5. ^ WO application 9214843, Toole, John J.; Griffin, Linda C. & Bock, Louis C. et al., "Aptamer specific for biomolecules and method of making", published 1992-09-03, assigned to Gilead Sciences Inc. 
  6. ^ Bock, Louis C.; Griffin, Linda C.; Latham, John A.; Vermaas, Eric H.; Toole, John J. (1992). "Selection of single-stranded DNA molecules that bind and inhibit human thrombin". Nature. 355 (6360): 564–566. Bibcode:1992Natur.355..564B. doi:10.1038/355564a0. PMID 1741036. S2CID 4349607.
  7. ^ Paborsky, L. R.; McCurdy, S. N.; Griffin, L. C.; Toole, J. J.; Leung, L. L. (1993-10-05). "The single-stranded DNA aptamer-binding site of human thrombin". The Journal of Biological Chemistry. 268 (28): 20808–20811. doi:10.1016/S0021-9258(19)36856-5. ISSN 0021-9258. PMID 8407909.
  8. ^ Griffin, L. C.; Tidmarsh, G. F.; Bock, L. C.; Toole, J. J.; Leung, L. L. (1993-06-15). "In vivo anticoagulant properties of a novel nucleotide-based thrombin inhibitor and demonstration of regional anticoagulation in extracorporeal circuits". Blood. 81 (12): 3271–3276. doi:10.1182/blood.V81.12.3271.3271. ISSN 0006-4971. PMID 8507864.
  9. ^ Shaw, Jeng‐Pyng; Fishback, James A.; Cundy, Kenneth C.; Lee, William A. (1995). "A Novel Oligodeoxynucleotide Inhibitor of Thrombin. I. In Vitro Metabolic Stability in Plasma and Serum". Pharmaceutical Research. 12 (12): 1937–1942. doi:10.1023/A:1016243923195. PMID 8786969. S2CID 9568739.
  10. ^ Lee, William A.; Fishback, James A.; Shaw, Jeng‐Pyng; Bock, Louis C.; Griffin, Linda C.; Cundy, Kenneth C. (1995). "A Novel Oligodeoxynucleotide Inhibitor of Thrombin. II. Pharmacokinetics in the Cynomolgus Monkey". Pharmaceutical Research. 12 (12): 1943–1947. doi:10.1023/A:1016295907266. PMID 8786970. S2CID 39428612.
  11. ^ Matsui, Shinobu; Fu, Michael L.X. (1998). "Myocardial injury due to G-protein coupled receptor-autoimmunity". Japanese Heart Journal. 39 (3): 261–274. doi:10.1536/ihj.39.261. PMID 9711178. S2CID 22133040.
  12. ^ Jahns, Roland; Boivin, Valérie; Siegmund, Christian; et al. (1999-02-09). "Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure". Circulation. 99 (5): 649–654. doi:10.1161/01.cir.99.5.649. PMID 9950662.
  13. ^ Okazaki, Taku; Honjo, Tasuku (2005). "Pathogenic roles of cardiac autoantibodies in dilated cardiomyopathy". Trends in Molecular Medicine. 11 (7): 322–326. doi:10.1016/j.molmed.2005.05.001. PMID 15935731.
  14. ^ Levin, Mariano J.; Hoebeke, Johan (2008-07-07). "Cross-talk between anti-beta1-adrenoceptor antibodies in dilated cardiomyopathy and Chagas' heart disease". Autoimmunity. 41 (6): 429–433. doi:10.1080/08916930802031702. PMID 18781468. S2CID 46169536.
  15. ^ Bornholz, B.; Wallukat, G.; Roggenbuck, D.; Schimke, I. (2017-02-17). "Chapter 3 - Autoantibodies Directed Against G-Protein-Coupled Receptors in Cardiovascular Diseases: Basics and Diagnostics". In Nussinovitch, Udi (ed.). The Heart in Rheumatic, Autoimmune and Inflammatory Diseases. Academic Press. pp. 49–63. doi:10.1016/B978-0-12-803267-1.00003-X. ISBN 978-0-12-803267-1.
  16. ^ Wallukat, Gerd; Müller, Johannes; Hetzer, Roland (2002-11-28). "Specific removal of beta1-adrenergic autoantibodies from patients with idiopathic dilated cardiomyopathy". The New England Journal of Medicine. 347 (22): 1806. doi:10.1056/NEJM200211283472220. PMID 12456865.
  17. ^ Doesch, Andreas O.; Konstandin, Mathias; Celik, Sultan; et al. (2009-07-09). "Effects of protein A immunoadsorption in patients with advanced chronic dilated cardiomyopathy". Journal of Clinical Apheresis. 24 (4): 141–149. doi:10.1002/jca.20204. PMID 19591221. S2CID 5566530.
  18. ^ Haberland, Ann; Wallukat, Gerd; Schimke, Ingolf (2013-02-26). "The patent situation concerning the treatment of diseases associated with autoantibodies directed against G-protein-coupled receptors". Pharmaceutical Patent Analyst. 2 (2): 231–248. doi:10.4155/ppa.12.88. PMID 24237028.
  19. ^ Patel, Priyesh A.; Hernandez, Adrian F. (2014-01-27). "Targeting anti-beta-1-adrenergic receptor antibodies for dilated cardiomyopathy". European Journal of Heart Failure. 15 (7): 724–729. doi:10.1093/eurjhf/hft065. PMC 3707431. PMID 23639780.
  20. ^ Haberland, Annekathrin; Holtzhauer, Martin; Schlichtiger, Alice; et al. (2016-10-15). "Aptamer BC 007 – A broad spectrum neutralizer of pathogenic autoantibodies against G-protein-coupled receptors". European Journal of Pharmacology. 789: 37–45. doi:10.1016/j.ejphar.2016.06.061. PMID 27375076.
  21. ^ Wallukat, Gerd; Müller, Johannes; Haberland, Annekathrin; et al. (2016). "Aptamer BC007 for neutralization of pathogenic autoantibodies directed against G-protein coupled receptors: A vision of future treatment of patients with cardiomyopathies and positivity for those autoantibodies". Atherosclerosis. 244: 44–47. doi:10.1016/j.atherosclerosis.2015.11.001. PMID 26584137.
  22. ^ Dale A (2018-03-01). "Just a Single Dose of this Drug Boosts the Survival of Heart Failure Patients". Labiotech. Retrieved 30 May 2023.
  23. ^ "Berlin Cures Announces Successful Completion of Phase 1 Study of BC 007 for the Treatment of Cardiomyopathy". BioSpace. 22 August 2018. Retrieved 30 May 2023.
  24. ^ Düngen HD, Dordevic A, Felix SB, Pieske B, Voors AA, McMurray JJ, Butler J (January 2020). "β1-Adrenoreceptor Autoantibodies in Heart Failure: Physiology and Therapeutic Implications". Circulation. Heart Failure. 13 (1): e006155. doi:10.1161/CIRCHEARTFAILURE.119.006155. PMID 31957469. S2CID 210831160.
  25. ^ Tan, Kei Xian; Jeevanandam, Jaison; Rodrigues, João; Danquah, Michael K. (2022-11-15). "Aptamer-Mediated Antiviral Approaches for SARS-CoV-2". Frontiers in Bioscience. 27 (11): 306. doi:10.31083/j.fbl2711306. PMID 36472112. S2CID 253602931.
  26. ^ Amini, Ryan; Zhang, Zijie; Li, Jiuxing; et al. (2022). "Aptamers for SARS-CoV-2: Isolation, Characterization, and Diagnostic and Therapeutic Developments". Analysis & Sensing. 2 (5): e202200012. doi:10.1002/anse.202200012. PMC 9082509. PMID 35574520.
  27. ^ Zhang, Yang; Juhas, Mario; Kwok, Chun Kit (2023). "Aptamers targeting SARS-COV-2: a promising tool to fight against COVID-19". Trends in Biotechnology. 41 (4): 528–544. doi:10.1016/j.tibtech.2022.07.012. PMC 9340053. PMID 35995601.
  28. ^ Davis, Hannah E.; McCorkell, Lisa; Vogel, Julia Moore; Topol, Eric J. (2023). "Long COVID: major findings, mechanisms and recommendations". Nature Reviews Microbiology. 21 (3): 133–146. doi:10.1038/s41579-022-00846-2. ISSN 1740-1534.


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