BC-007

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.

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 mass4806.062 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

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]

COVID-19 and long COVID

BC-007 is under investigation as a possible agent for treating COVID-19 infection and disorders of long COVID.[25][26]

References
  1. 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. 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. PMC 9839201. PMID 36639608.
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