Islatravir

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Islatravir
Islatravir.svg
Names
IUPAC name
2′-Deoxy-4′-ethynyl-2-fluoroadenosine
Preferred IUPAC name
(2R,3S,5R)-5-(6-Amino-2-fluoro-9H-purin-9-yl)-2-ethynyl-2-(hydroxymethyl)oxolan-3-ol
Other names
EFdA; MK-8591; 4′-Ethynyl-2-fluoro-2′-deoxyadenosine
Identifiers
3D model (JSmol)
ChemSpider
UNII
  • InChI=1S/C12H12FN5O3/c1-2-12(4-19)6(20)3-7(21-12)18-5-15-8-9(14)16-11(13)17-10(8)18/h1,5-7,19-20H,3-4H2,(H2,14,16,17)/t6-,7+,12+/m0/s1
    Key: IKKXOSBHLYMWAE-QRPMWFLTSA-N
  • C#C[C@]1([C@H](C[C@@H](O1)n2cnc3c2nc(nc3N)F)O)CO
Properties
C12H12FN5O3
Molar mass 293.258 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

Islatravir (4′-ethynyl-2-fluoro-2′-deoxyadenosine, EFdA, or MK-8591) is an investigational drug for the treatment of HIV infection.[1] It is classified as a nucleoside reverse transcriptase translocation inhibitor (NRTTI).[2] Merck is developing a subdermal drug-eluting implant to administer islatravir.[3][4]

Biological activity

Islatravir has activity against HIV in animal models,[5] and is being studied clinically for HIV treatment and prophylaxis.[6] Islatravir is a nucleoside analog reverse transcriptase translocation inhibitor that unlike other such inhibitors, inhibits HIV through multiple mechanisms,[5] providing rapid suppression of the virus, when tested in macaques and mice.[7] Nevertheless, there are HIV strains resistant to islatravir and research is ongoing.[8][9]

References

  1. ^ Kawamoto, A; Kodama, E; Sarafianos, SG; Sakagami, Y; Kohgo, S; Kitano, K; Ashida, N; Iwai, Y; Hayakawa, H; Nakata, H; Mitsuya, H; Arnold, E; Matsuoka, M (2008). "2'-deoxy-4'-C-ethynyl-2-halo-adenosines active against drug-resistant human immunodeficiency virus type 1 variants". The International Journal of Biochemistry & Cell Biology. 40 (11): 2410–20. doi:10.1016/j.biocel.2008.04.007. PMID 18487070.
  2. ^ Roy M. Gulick (2018). "Investigational Antiretroviral Drugs: What is Coming Down the Pipeline". Top Antivir Med. 25 (4): 127–132. PMC 5935216. PMID 29689540.
  3. ^ "Someday, an Arm Implant May Prevent H.I.V. Infection for a Year". New York Times. July 23, 2019.
  4. ^ "Merck Presents Early Evidence on Extended Delivery of Investigational Anti-HIV-1 Agent Islatravir (MK-8591) via Subdermal Implant" (Press release). July 23, 2019.
  5. ^ a b Michailidis, Eleftherios; Huber, Andrew D.; Ryan, Emily M.; Ong, Yee T.; Leslie, Maxwell D.; Matzek, Kayla B.; Singh, Kamalendra; Marchand, Bruno; Hagedorn, Ariel N.; Kirby, Karen A.; Rohan, Lisa C.; Kodama, Eiichi N.; Mitsuya, Hiroaki; Parniak, Michael A.; Sarafianos, Stefan G. (2014). "4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) Inhibits HIV-1 Reverse Transcriptase with Multiple Mechanisms". Journal of Biological Chemistry. 289 (35): 24533–48. doi:10.1074/jbc.M114.562694. PMC 4148878. PMID 24970894.
  6. ^ Grobler, Jay (February 22–25, 2016). Long-Acting Oral and Parenteral Dosing of MK-8591 for HIV Treatment or Prophylaxis. Boston, Massachusetts. Conference on Retroviruses and Opportunistic Infections. 98.
  7. ^ Stoddart, Cheryl A.; Galkina, Sofiya A.; Joshi, Pheroze; Kosikova, Galina; Moreno, Mary E.; Rivera, Jose M.; Sloan, Barbara; Reeve, Aaron B.; Sarafianos, Stefan G.; Murphey-Corb, Michael; Parniak, Michael A. (2015). "Oral Administration of the Nucleoside EFdA (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Provides Rapid Suppression of HIV Viremia in Humanized Mice and Favorable Pharmacokinetic Properties in Mice and the Rhesus Macaque". Antimicrobial Agents and Chemotherapy. 59 (7): 4190–8. doi:10.1128/AAC.05036-14. PMC 4468726. PMID 25941222.
  8. ^ Bruno Marchand. "The Crystal Structure of EFdA‐Resistant HIV‐1 Reverse Transcriptase Reveals Structural Changes in the Polymerase Active Site" (PDF).
  9. ^ Salie, Zhe Li; Kirby, Karen A.; Michailidis, Eleftherios; Marchand, Bruno; Singh, Kamalendra; Rohan, Lisa C.; Kodama, Eiichi N.; Mitsuya, Hiroaki; Parniak, Michael A.; Sarafianos, Stefan G. (16 August 2016). "Structural basis of HIV inhibition by translocation-defective RT inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA)". Proceedings of the National Academy of Sciences. 113 (33): 9274–9279. doi:10.1073/pnas.1605223113. PMC 4995989. PMID 27489345.