Bulevirtide

Bulevirtide, sold under the brand name Hepcludex, is an antiviral medication for the treatment of chronic hepatitis D (in the presence of hepatitis B).[3]

Bulevirtide
Clinical data
Trade namesHepcludex
Other namesMyrB, Myrcludex-B[1]
License data
Routes of
administration		Subcutaneous
ATC code
Legal status
Legal status
  • UK: POM (Prescription only) [2]
  • EU: Rx-only [3]
Identifiers
CAS Number
DrugBank
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC248H355N65O72
Molar mass5398.951 g·mol−1
3D model (JSmol)
SMILES
  • CCCCCCCCCCCCCC(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(=O)NCC(N)=O)C(C)C)C(C)C)[C@@H](C)O
InChI
  • InChI=1S/C248H355N65O72/c1-16-17-18-19-20-21-22-23-24-25-38-75-193(327)265-118-196(330)304-205(133(15)316)241(378)295-163(104-188(256)322)224(361)283-152(91-127(6)7)216(353)303-175(122-315)232(369)306-204(129(10)11)248(385)313-88-53-74-182(313)239(376)301-172(107-191(259)325)246(383)312-87-50-70-178(312)235(372)291-150(89-125(2)3)209(346)268-120-195(329)274-154(93-135-56-32-27-33-57-135)217(354)296-168(95-137-60-36-29-37-61-137)242(379)308-83-49-72-180(308)237(374)294-167(111-201(339)340)230(367)286-157(98-140-115-261-123-269-140)220(357)277-148(76-78-183(251)317)213(350)282-151(90-126(4)5)215(352)300-173(112-202(341)342)247(384)307-82-47-68-176(307)233(370)273-132(14)208(345)279-153(92-134-54-30-26-31-55-134)210(347)267-119-194(328)271-130(12)206(343)280-160(101-185(253)319)226(363)302-174(121-314)231(368)288-161(102-186(254)320)225(362)299-171(106-190(258)324)245(382)311-86-52-73-181(311)238(375)293-166(110-200(337)338)229(366)285-156(96-138-113-263-144-64-41-39-62-142(138)144)219(356)290-165(109-199(335)336)227(364)284-155(94-136-58-34-28-35-59-136)218(355)298-170(105-189(257)323)244(381)310-85-51-71-179(310)236(373)292-162(103-187(255)321)223(360)275-146(66-43-45-80-249)212(349)289-164(108-198(333)334)228(365)287-158(99-141-116-262-124-270-141)221(358)297-169(97-139-114-264-145-65-42-40-63-143(139)145)243(380)309-84-48-69-177(309)234(371)278-149(77-79-197(331)332)211(348)272-131(13)207(344)281-159(100-184(252)318)222(359)276-147(67-44-46-81-250)214(351)305-203(128(8)9)240(377)266-117-192(260)326/h26-37,39-42,54-65,113-116,123-133,146-182,203-205,263-264,314-316H,16-25,38,43-53,66-112,117-122,249-250H2,1-15H3,(H2,251,317)(H2,252,318)(H2,253,319)(H2,254,320)(H2,255,321)(H2,256,322)(H2,257,323)(H2,258,324)(H2,259,325)(H2,260,326)(H,261,269)(H,262,270)(H,265,327)(H,266,377)(H,267,347)(H,268,346)(H,271,328)(H,272,348)(H,273,370)(H,274,329)(H,275,360)(H,276,359)(H,277,357)(H,278,371)(H,279,345)(H,280,343)(H,281,344)(H,282,350)(H,283,361)(H,284,364)(H,285,366)(H,286,367)(H,287,365)(H,288,368)(H,289,349)(H,290,356)(H,291,372)(H,292,373)(H,293,375)(H,294,374)(H,295,378)(H,296,354)(H,297,358)(H,298,355)(H,299,362)(H,300,352)(H,301,376)(H,302,363)(H,303,353)(H,304,330)(H,305,351)(H,306,369)(H,331,332)(H,333,334)(H,335,336)(H,337,338)(H,339,340)(H,341,342)/t130-,131-,132-,133+,146-,147-,148-,149-,150-,151-,152-,153-,154-,155-,156-,157-,158-,159-,160-,161-,162-,163-,164-,165-,166-,167-,168-,169-,170-,171-,172-,173-,174-,175-,176-,177-,178-,179-,180-,181-,182-,203-,204-,205-/m0/s1
  • Key:WQNDXLHKAMIGEX-WOAPPVHJSA-N

The most common side effects include raised levels of bile salts in the blood and reactions at the site of injection.[3]

Bulevirtide works by attaching to and blocking a receptor (target) through which the hepatitis delta and hepatitis B viruses enter liver cells.[3] By blocking the entry of the virus into the cells, it limits the ability of HDV to replicate and its effects in the body, reducing symptoms of the disease.[3]

Bulevirtide was approved for medical use in the European Union in July 2020.[3]

Structural formula

Bulevirtide is a 47-amino acid peptide with the following sequence:[4]

CH3(CH2)12CO-Gly-Thr-Asn-Leu-Ser-Val-Pro-Asn-Pro-Leu-Gly-Phe-Phe-Pro-Asp-His-Gln-Leu-Asp-Pro-Ala-Phe-Gly-Ala-Asn-Ser-Asn-Asn-Pro-Asp-Trp-Asp-Phe-Asn-Pro-Asn-Lys-Asp-His-Trp-Pro-Glu-Ala-Asn-Lys-Val-Gly-NH2 (C13H27CO-GTNLSVPNPLGFFPDHQLDPAFGANSNNPDWDFNPNKDHWPEANKVG-NH2)

Medical uses

Bulevirtide is indicated for the treatment of chronic hepatitis delta virus (HDV) infection in plasma (or serum) HDV-RNA positive adult patients with compensated liver disease.[3][5]

Pharmacology

Mechanism of action

Bulevirtide binds and inactivates the sodium/bile acid cotransporter, blocking both viruses from entering hepatocytes.[6]

The hepatitis B virus uses its surface lipopeptide pre-S1 for docking to mature liver cells via their sodium/bile acid cotransporter (NTCP) and subsequently entering the cells. Myrcludex B is a synthetic N-acylated pre-S1[7][8] that can also dock to NTCP, blocking the virus's entry mechanism.[9]

The drug is also effective against hepatitis D because the hepatitis D virus is only infective in the presence of a hepatitis B virus infection.[9]

References
  1. Deterding, K.; Wedemeyer, H. (2019). "Beyond Pegylated Interferon-Alpha: New Treatments for Hepatitis Delta". AIDS Reviews. 21 (3): 126–134. doi:10.24875/AIDSRev.19000080. PMID 31532397. S2CID 202674681.
  2. "Hepcludex 2 mg powder for solution for injection - Summary of Product Characteristics (SmPC)". (emc). 30 March 2022. Retrieved 1 July 2022.
  3. "Hepcludex EPAR". European Medicines Agency (EMA). 26 May 2020. Retrieved 12 August 2020. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  4. Sauter M, Blank A, Stoll F, Lutz N, Haefeli WE, Burhenne J (May 2021). "Intact plasma quantification of the large therapeutic lipopeptide bulevirtide". Analytical and Bioanalytical Chemistry. 413 (22): 5645–54. doi:10.1007/s00216-021-03384-7. PMC 8410713. PMID 34018034.
  5. "Summary of opinion: Hepcludex" (PDF). European Medicines Agency. 28 May 2020.
  6. Francisco, Estela Miranda (29 May 2020). "Hepcludex". European Medicines Agency. Archived from the original on 15 June 2020. Retrieved 6 August 2020.
  7. Volz T, Allweiss L, Ben MBarek M, Warlich M, Lohse AW, Pollok JM, et al. (May 2013). "The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus". Journal of Hepatology. 58 (5): 861–7. doi:10.1016/j.jhep.2012.12.008. PMID 23246506.
  8. Abbas Z, Abbas M (August 2015). "Management of hepatitis delta: Need for novel therapeutic options". World Journal of Gastroenterology. 21 (32): 9461–5. doi:10.3748/wjg.v21.i32.9461. PMC 4548107. PMID 26327754.
  9. Spreitzer H (14 September 2015). "Neue Wirkstoffe – Myrcludex B". Österreichische Apothekerzeitung (in German) (19/2015): 12.
  • "Bulevirtide". Drug Information Portal. U.S. National Library of Medicine.


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