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Highly active antiretroviral therapy

Breakthrough in HIV/AIDS Treatment: Lenacapavir Shown to be Effective Against Multidrug-Resistant HIV-1

Strategic Insights

— 1 min read

Researchers from Ohio State University have made a significant discovery in the field of HIV/AIDS treatment, revealing that Lenacapavir (LEN), a new, first-in-class, long-acting HIV-1 capsid-targeting inhibitor, exhibits high potency against all major HIV-1 subtypes, including variants resistant to current antiretroviral therapies. The study, published in the ACS Medicinal Chemistry Letters, demonstrates that LEN has a relatively low barrier to viral resistance, necessitating continued efforts to develop next-generation inhibitors against emerging LEN-resistant mutations. The researchers have identified a new LEN analog, KFA-027, with substantially improved antiviral activity against the M66I variant, a mutation that exhibits the highest level of resistance to LEN.

Key Takeaways:

  • Lenacapavir (LEN) is a new, first-in-class, long-acting HIV-1 capsid-targeting inhibitor with high potency against all major HIV-1 subtypes.
  • LEN has a relatively low barrier to viral resistance, with the M66I variant exhibiting the highest level of resistance (3200-fold).
  • The researchers have identified a new LEN analog, KFA-027, with substantially improved antiviral activity (EC50 of 444 nM, 20-fold) against the M66I variant.
  • The study highlights the need for continued research to develop next-generation inhibitors against emerging LEN-resistant mutations.
  • The study was funded by the NIH National Institute of Allergy & Infectious Diseases (NIAID).
  • The research has been peer-reviewed and published in the ACS Medicinal Chemistry Letters.

Statistics:

  • The M66I variant exhibits a 3200-fold level of resistance to LEN.
  • The new LEN analog, KFA-027, has an EC50 of 444 nM, which is 20-fold improved over LEN against the M66I variant.
  • The study was funded by the NIH National Institute of Allergy & Infectious Diseases (NIAID).

Sources:

  • Delineating Structural Functionalities of Lenacapavir Amenable To Modifications for Targeting Emerging Drug-resistant Hiv-1 Capsid Variants. Acs Medicinal Chemistry Letters, 2025.
  • Ohio State University, College of Pharmacy, Division of Medicinal Chemistry and Pharmacognosy, Columbus, OH 43210, United States.
  • American Chemical Society (ACS) - www.acs.org; Acs Medicinal Chemistry Letters - www.pubs.acs.org/journal/amclct
  • Jeffrey R. Lockwood, Ross H. Bockbrader, Arun S. Annamalai, Tung Dinh, Reed Haney, and Mamuka Kvaratskhelia.

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