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| Names | |
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| IUPAC name 2′-Deoxy-4′-ethynyl-2-fluoroadenosine | |
| Systematic 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 | |
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| 3D model (JSmol) | |
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| Properties | |
| Chemical formula | C12H12FN5O3 |
| Molar mass | 293.258 g·mol |
| Except where otherwise noted, data are given for materials in their standard state (at 25 °C , 100 kPa). Infobox references | |
Islatravir (4′-ethynyl-2-fluoro-2′-deoxyadenosine, EFdA, or MK-8591) is an investigational drug for the treatment of HIV infection. It is classified as a nucleoside reverse transcriptase translocation inhibitor (NRTTI). Merck is developing a subdermal drug-eluting implant to administer islatravir.
In 2021, FDA placed a partial clinical hold for several studies under Islatravir. The reason was a decline in CD4 T cells under therapy. Merck announced to restart the study program in 2023 with a decreased dose, however studies of islatravir for pre-exposure prophylaxis (PrEP) will be discontinued.
In 2024, results from a phase II study combining islatravir with lenacapavir indicated that the regimen shows promise as a possible weekly oral regimen.
Biological activity
Islatravir has activity against HIV in animal models, and is being studied clinically for HIV treatment and prophylaxis. Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that unlike other such inhibitors, inhibits HIV through multiple mechanisms, providing rapid suppression of the virus, when tested in macaques and mice. Nevertheless, there are HIV strains resistant to islatravir and research is ongoing.
References
- 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.
- Roy M. Gulick (2018). "Investigational Antiretroviral Drugs: What is Coming Down the Pipeline". Top Antivir Med. 25 (4): 127–132. PMC 5935216. PMID 29689540.
- "Someday, an Arm Implant May Prevent H.I.V. Infection for a Year". New York Times. July 23, 2019.
- "Merck Presents Early Evidence on Extended Delivery of Investigational Anti-HIV-1 Agent Islatravir (MK-8591) via Subdermal Implant" (Press release). July 23, 2019.
- "Merck restarts islatravir HIV treatment studies, but abandons monthly PrEP". aidsmap.com. Retrieved 2023-05-02.
- "Merck to Initiate New Phase 3 Clinical Program with Lower Dose of Daily Oral Islatravir in Combination with Doravirine for Treatment of People with HIV-1 Infection". Merck. Retrieved 10 March 2024.
- Highleyman, Liz (6 March 2024). "Islatravir plus lenacapavir could be the first once-weekly oral HIV treatment". Aidsmap. Retrieved 10 March 2024.
- ^ 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.
- 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.
- 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.
- Bruno Marchand. "The Crystal Structure of EFdA‐Resistant HIV‐1 Reverse Transcriptase Reveals Structural Changes in the Polymerase Active Site" (PDF).
- 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.