Miravirsen

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File:Miravirsen.png
Systematic (IUPAC) name
RNA, (P-thio)((2'-O,4'-C-methylene)m5C-dC-(2'-O,4'-C-methylene)A-dT-dT-(2'-O,4'-C-methylene)G-(2'-O,4'-C-methylene)m5U-dC-dA-(2'-O,4'-C-methylene)m5C-dA-(2'-O,4'-C-methylene)m5C-dT-(2'-O,4'-C-methylene)m5C-(2'-O,4'-C-methylene)m5C)
Clinical data
Legal status
  • Investigational
Routes of
administration		 Intravenous or subcutaneous injection
Identifiers
CAS Number 1072874-90-8
ATC code none
PubChem CID: 56843415
Synonyms SPC3649
Chemical data
Formula C151H185N49O83P14S14
Molecular mass 4,896.87 g·mol−1
  • CC1=CN(C(=O)NC1=O)C2CC(C(O2)COP(=S)(O)OC3C4C(OC3(CO4)COP(=S)(O)OC5CC(OC5COP(=S)(O)OC6C7C(OC6(CO7)CO)N8C=CC(=NC8=O)N)N9C=CC(=NC9=O)N)N1C=NC2=C1N=CN=C2N)OP(=S)(O)OCC1C(CC(O1)N1C=C(C(=O)NC1=O)C)OP(=S)(O)OCC12COC(C1OP(=S)(O)OCC13COC(C1OP(=S)(O)OCC1C(CC(O1)N1C=CC(=NC1=O)N)OP(=S)(O)OCC1C(CC(O1)N1C=NC4=C1N=CN=C4N)OP(=S)(O)OCC14COC(C1OP(=S)(O)OCC1C(CC(O1)N1C=NC5=C1N=CN=C5N)OP(=S)(O)OCC15COC(C1OP(=S)(O)OCC1C(CC(O1)N1C=C(C(=O)NC1=O)C)OP(=S)(O)OCC16COC(C1OP(=S)(O)OCC17COC(C1O)C(O7)N1C=CC(=NC1=O)N)C(O6)N1C=CC(=NC1=O)N)C(O5)N1C=CC(=NC1=O)N)C(O4)N1C=CC(=NC1=O)N)C(O3)N1C=C(C(=O)NC1=O)C)C(O2)N1C=NC2=C1N=C(NC2=O)N
  • InChI=1S/C151H185N49O83P14S14/c1-60-26-193(140(215)182-119(60)203)87-21-66(74(258-87)34-245-290(225,304)281-110-102-130(199-58-171-94-114(161)165-55-168-117(94)199)268-150(110,44-239-102)50-252-291(226,305)272-65-20-86(187-13-6-79(153)174-134(187)209)256-72(65)33-243-286(221,300)277-105-97-125(262-144(105,37-201)38-234-97)189-15-8-81(155)176-136(189)211)271-285(220,299)241-30-73-67(22-88(257-73)194-27-61(2)120(204)183-141(194)216)273-293(228,307)253-51-151-45-240-103(131(269-151)200-59-172-95-118(200)180-132(162)181-123(95)207)111(151)283-297(232,311)254-52-149-43-238-101(129(267-149)196-29-63(4)122(206)185-143(196)218)109(149)280-289(224,303)244-32-71-64(19-85(255-71)186-12-5-78(152)173-133(186)208)270-284(219,298)242-31-76-69(24-90(260-76)197-56-169-92-112(159)163-53-166-115(92)197)275-294(229,308)249-47-147-41-236-99(127(265-147)191-17-10-83(157)178-138(191)213)107(147)279-288(223,302)247-36-77-70(25-91(261-77)198-57-170-93-113(160)164-54-167-116(93)198)276-295(230,309)250-48-146-40-235-98(126(264-146)190-16-9-82(156)177-137(190)212)106(146)278-287(222,301)246-35-75-68(23-89(259-75)195-28-62(3)121(205)184-142(195)217)274-292(227,306)251-49-148-42-237-100(128(266-148)192-18-11-84(158)179-139(192)214)108(148)282-296(231,310)248-46-145-39-233-96(104(145)202)124(263-145)188-14-7-80(154)175-135(188)210/h5-18,26-29,53-59,64-77,85-91,96-111,124-131,201-202H,19-25,30-52H2,1-4H3,(H,219,298)(H,220,299)(H,221,300)(H,222,301)(H,223,302)(H,224,303)(H,225,304)(H,226,305)(H,227,306)(H,228,307)(H,229,308)(H,230,309)(H,231,310)(H,232,311)(H2,152,173,208)(H2,153,174,209)(H2,154,175,210)(H2,155,176,211)(H2,156,177,212)(H2,157,178,213)(H2,158,179,214)(H2,159,163,166)(H2,160,164,167)(H2,161,165,168)(H,182,203,215)(H,183,204,216)(H,184,205,217)(H,185,206,218)(H3,162,180,181,207)
  • Key:OSOOBMBDIGGTCP-UHFFFAOYSA-N

Miravirsen (INN; codenamed SPC3649) is an experimental drug for the treatment of hepatitis C, being developed by Santaris Pharma.

Mechanism of action

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Further information: miR-122 § Regulation of HCV

Miravirsen is a short modified RNA molecule that is applied by intravenous or subcutaneous[1] injection. It reaches the liver and binds to the human microRNA called miR-122; this mechanism makes it an antisense RNA.[2] The hepatitis C virus needs miR-122 to multiply, but cannot utilise it if bound by miravirsen.[3]

Potential side effects

As miR-122 has tumour protective properties in liver cells,[4][5] concerns about a possible risk of hepatic cancer have been voiced.[6] The drug did not induce liver toxicity in non-human primates,[2] nor in a human study.[1]

Chemical properties

Chemical structure of a single nucleoside (sugar plus base) of a locked nucleic acid

Miravirsen is a modified oligonucleotide consisting of a chain of 15 nucleotides, the base sequence of which is designed to selectively bind to miR-122.[6][7] Seven of the 15 sugar units are desoxyriboses, and the other eight are riboses with an additional bridge between the 2' oxygen and the 4' carbon atoms; this makes the molecule a locked nucleic acid. Furthermore, the phosphate units have been replaced by thiophosphates.[7]

The complete base sequence is

mC*-dC-A*-dT-dT-G*-mU*-dC-dA-mC*-dA-mC*-dT-mC*-mC* [d = 2'-deoxy, * = 2'-O,4'-C-methylene, i.e. bridged or "locked" sugar]

with 3'→5' thiophosphate linkages.[7]

Research

Miravirsen reduced HCV viremia in a small-scale trial in chimpanzees[8] and was found to be safe in a clinical trial in 27 humans over eight to eleven weeks.[1]

The drug underwent a Phase IIa trial in which patients were randomly assigned to placebo groups or one of the three multiple ascending dose groups (3 mg/kg, 5 mg/kg, 7 mg/kg of miravirsen). The naïve patients were given 5 weekly doses of miravirsen via subcutaneous injection for four weeks, and 4 out of 9 patients receiving the highest dose (7 mg/kg) exhibited significant decrease in hepatitis C virus RNA (p<0.001). The result was sustained even 10 weeks after the last miravirsen administration.[3][9]

References

  1. ↑ 1.0 1.1 1.2 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ 2.0 2.1 Lua error in package.lua at line 80: module 'strict' not found.
  3. ↑ 3.0 3.1 Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ 6.0 6.1 Schubert-Zsilavecz, M, Wurglics, M, Neue Arzneimittel Herbst 2015.
  7. ↑ 7.0 7.1 7.2 PubChem: Miravirsen
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
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