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BC-007

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BC-007
INN: Rovunaptabin
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
  • ODN1, ODN-1
  • 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

BC-007, whose international nonproprietary name is Rovunaptabin,[1] is an oligonucleotide aptamer, a synthetic DNA compound designed to bind other chemicals.[2] BC-007 is in early-stage clinical trials as a lead compound intended for the potential treatment of heart failure or long COVID.

History

[edit]

Since the 1990s, the binding of G protein coupled receptors to autoantibodies (GPCR-AABs) was investigated as a possible factor in the pathology of several diseases, including heart disease.[3][4] In parallel, treatment strategies to remove GPCR-AABs were investigated, initially using proteins or peptides to bind the antibodies.[5][6]

In 2012, scientists from the Max Delbrück Center and the Charité Heart Center obtained a patent in the United States for using aptamers as a therapy or diagnosis of autoimmune diseases.[7] Beginning in 2013, the research group focused on the treatment of dilated cardiomyopathy in people positive for beta-1 adrenergic receptor autoantibodies.[8][9] In 2015–16, scientists reported that two aptamers might bind and inhibit GPCR-AABs.[10][11]

The biotechnology company Berlin Cures pursued the development of the aptamer with the nucleotide sequence GGT TGG TGT GGT TGG under the codename BC-007 for the inhibition of autoantibodies in cardiomyopathy.[12]

Properties

[edit]

BC-007 is a 15-nucleotide single-stranded DNA molecule consisting of nine unmodified deoxy-guanosines and six corresponding deoxythymidines with the sequence 5'-GGT TGG TGT GGT TGG-3'.[2] Its three-dimensional structure allows it to wrap around the target structure of G-protein-coupled receptor autoantibodies and neutralize their activity.[2]

BC-007 is synthetic, enabling it to be produced in high volumes quickly.[13] It is stable and suited for long-term storage.[13] It has shown no side effects in early clinical studies, and does not trigger immunological responses.[2][13] As it is water soluble, it can be formulated as inhalation or as nasal spray.[13] In some human studies, it was given by intravenous infusion, displaying an in vivo half-life in blood of about 4 minutes.[2]

Research

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Heart failure

[edit]

The removal of pathogenic functional autoantibodies through a medical blood purification procedure, known as immunoadsorption, can stabilize heart function in people with dilated cardiomyopathy who are awaiting heart transplantation.[14][15] In 2018, a Phase I clinical trial found that BC-007 was well-tolerated, with no serious adverse events reported.[2][12] Phase IIa trials demonstrated that BC-007 could neutralize the activity of functional autoantibodies in most subjects treated.[16]

Long COVID

[edit]

BC-007 is under investigation as a possible agent for treating disorders of long COVID.[17]

References

[edit]
  1. ^ "WHO Drug Information - International Nonproprietary Names for Pharmaceutical Substances (INN) - Recommended INN: List 91". INN and Classification of Medical Products (INN), World Health Organization. 2024-03-25. Archived from the original (PDF) on 2024-03-25. Retrieved 2024-04-03.
  2. ^ a b c d e f Kolter T (2023). "BC-007". In Böckler F, Dill B, Eisenbrand G, et al. (eds.). Römpp [Online]. Georg Thieme Verlag. Archived from the original on 2023-07-23.
  3. ^ Matsui S, Fu ML (May 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.
  4. ^ 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 U (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.
  5. ^ Wallukat G, Müller J, Hetzer R (November 2002). "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.
  6. ^ Doesch AO, Konstandin M, Celik S, Kristen A, Frankenstein L, Hardt S, 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.
  7. ^ Büttner, Bettina (2012). "Technology offer - Aptamers for the Treatment and Diagnosis of Diseases Seropositive for Autoantibodies - Ref. No.: CH553" (PDF). Charité-Universitätsmedizin Berlin. Archived from the original (PDF) on 2023-04-23.
  8. ^ Haberland A, Wallukat G, Schimke I (March 2013). "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.
  9. ^ Patel PA, Hernandez AF (July 2013). "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.
  10. ^ Haberland A, Holtzhauer M, Schlichtiger A, Bartel S, Schimke I, Müller J, et al. (October 2016). "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.
  11. ^ Wallukat G, Müller J, Haberland A, Berg S, Schulz A, Freyse EJ, et al. (January 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.
  12. ^ a b "Berlin Cures Announces Successful Completion of Phase 1 Study of BC 007 for the Treatment of Cardiomyopathy". BioSpace. 2018-08-22. Archived from the original on 2023-05-30. Retrieved 2023-05-30.
  13. ^ a b c d Lang, Carolin (2020-07-08). "Wirkstoff-Kandidat auf DNA Basis - Mit James Bond gegen Covid-19" [Drug candidate based on DNA - Fighting Covid-19 with James Bond]. Pharmazeutische Zeitung (PZ) - Die Zeitschrift der deutschen Apotheker (in German). Avoxa - Mediengruppe Deutscher Apotheker GmbH. ISSN 0031-7136. Archived from the original on 2020-07-08. Retrieved 2024-04-09.
  14. ^ Werner S, Wallukat G, Becker NP, Wenzel K, Müller J, Schimke I, Wess G (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.
  15. ^ Dandel M, Wallukat G, Englert A, Lehmkuhl HB, Knosalla C, Hetzer R (December 2012). "Long-term benefits of immunoadsorption in β(1)-adrenoceptor autoantibody-positive transplant candidates with dilated cardiomyopathy". European Journal of Heart Failure. 14 (12): 1374–1388. doi:10.1093/eurjhf/hfs123. PMID 22892122.
  16. ^ 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.
  17. ^ Becker NP, Haberland A, Wenzel K, Göttel P, Wallukat G, Davideit H, 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.
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