Chemistry:Islatravir
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| Names | |
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| IUPAC name
2′-Deoxy-4′-ethynyl-2-fluoroadenosine
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| 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
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| Identifiers | |
3D model (JSmol)
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| ChemSpider | |
PubChem CID
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| UNII | |
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| 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). | |
| Infobox references | |
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]
In 2021, FDA placed a partial clinical hold for several studies under Islatravir.[5] 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.
Biological activity
Islatravir has activity against HIV in animal models,[6] and is being studied clinically for HIV treatment and prophylaxis.[7] Islatravir is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that unlike other such inhibitors, inhibits HIV through multiple mechanisms,[6] providing rapid suppression of the virus, when tested in macaques and mice.[8] Nevertheless, there are HIV strains resistant to islatravir and research is ongoing.[9][10]
References
- ↑ Kawamoto, A; Kodama, E; Sarafianos, SG; Sakagami, Y; Kohgo, S; Kitano, K; Ashida, N; Iwai, Y et al. (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. PMID 29689540.
- ↑ "Someday, an Arm Implant May Prevent H.I.V. Infection for a Year". New York Times. July 23, 2019. https://www.nytimes.com/2019/07/23/health/hiv-aids-implant.html.
- ↑ "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" (in en). https://www.aidsmap.com/news/sep-2022/merck-restarts-islatravir-hiv-treatment-studies-abandons-monthly-prep.
- ↑ 6.0 6.1 Michailidis, Eleftherios; Huber, Andrew D.; Ryan, Emily M.; Ong, Yee T.; Leslie, Maxwell D.; Matzek, Kayla B.; Singh, Kamalendra; Marchand, Bruno et al. (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. 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. http://www.croiconference.org/sessions/long-acting-oral-and-parenteral-dosing-mk-8591-hiv-treatment-or-prophylaxis.
- ↑ Stoddart, Cheryl A.; Galkina, Sofiya A.; Joshi, Pheroze; Kosikova, Galina; Moreno, Mary E.; Rivera, Jose M.; Sloan, Barbara; Reeve, Aaron B. et al. (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. PMID 25941222.
- ↑ Bruno Marchand. "The Crystal Structure of EFdA‐Resistant HIV‐1 Reverse Transcriptase Reveals Structural Changes in the Polymerase Active Site". http://www.ihlpress.com/pdf%20files/resistance10_presentations/04_Marchand.pdf.
- ↑ Salie, Zhe Li; Kirby, Karen A.; Michailidis, Eleftherios; Marchand, Bruno; Singh, Kamalendra; Rohan, Lisa C.; Kodama, Eiichi N.; Mitsuya, Hiroaki et al. (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. PMID 27489345.
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