Abstract
Ultra-long-acting (ULA) antiretroviral parenteral formulations, with low injection volumes, high resistance barriers, and short pharmacokinetic (PK) tails, can transform HIV-1 therapeutics. Here, we converted bictegravir (BIC), a potent daily oral antiretroviral drug, into monomeric and homodimeric ester prodrugs. The homodimeric prodrug nanosuspension, NMXBIC, shows sustained plasma BIC levels > 16 times the protein-adjusted 95% inhibitory concentration (PA-IC95) for six months after a single injection in Sprague Dawley rats. The results paralleled a short PK tail with the potential for late dose forgiveness. The monomeric prodrug nanosuspension, NM2BIC, shows lower year-long plasma BIC concentrations above PA-IC95 after a single injection. After repeated injections, NMXBIC and NM2BIC are well tolerated in New Zealand White rabbits. NMXBIC’s physicochemical properties and high BIC loading/unit mass of the prodrug contribute to its unique ULA PK profile. These results support its development as a ULA formulation for HIV-1 treatment and prevention.
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Source data are provided in the Figshare database under Digital Object Identifier. https://doi.org/10.6084/m9.figshare.30879314 (Fig. 1); https://doi.org/10.6084/m9.figshare.30879389 (Fig. 2); https://doi.org/10.6084/m9.figshare.30879395 (Fig. 3); https://doi.org/10.6084/m9.figshare.30879398 (Fig. 4); https://doi.org/10.6084/m9.figshare.30879437 (Fig. 5); https://doi.org/10.6084/m9.figshare.30881102 (Supplementary Materials). Source data are provided with this paper.
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Acknowledgements
The authors thank the University of Nebraska Medical Center (UNMC) cores for NMR (Ed Ezell), Elutriation and Cell Separation (Myhanh Che, Na Ly, and Li Wu), Electron Microscopy, Histology (Tissue Sciences Facility), MALDI/TOF Mass Spectrometry, as well as Comparative Medicine for technical assistance and animal care. The authors also wish to thank Gilead Sciences Inc. for designing and funding the injection site tolerability study in NZW rabbits performed at Labcorp Early Development Laboratories Inc. This research is supported by the University of Nebraska Foundation, which includes donations from the Carol Swarts, M.D. Emerging Neuroscience Research Laboratory, the Margaret R. Larson Professorship, the Frances and Louie Blumkin Endowment, the Community Pride of Nebraska Professorship, the Sylvia L. Havlik Centennial Professorship of Oncology, and the Harriet Singer Endowment; the Vice Chancellor’s Office of the University of Nebraska Medical Center for Core Facilities; Nickolus Badami Fellowship, The Nebraska Neuroscience Alliance Award, and the National Institutes of Health grants R01AI145542, R01AI158160, and R01AI163042.
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M.N.—study design, synthesized the prodrugs and formulations, design and execution of experiments, data acquisition, data analysis and interpretation, co-wrote manuscript; S.A. and A.K.D.—assisted with solid state data acquisition; C.Z., P.K.D., B.G., B.S., S. Das, and N.T.H.L.—assisted with animal PK and efficacy study data acquisition; B.H., A.S., and S. Deodhar—assisted with LC-MS/MS sample analyses; S.M.C.—acquisition and interpretation of toxicology data sets; H.E.G.—design of experiments; data interpretation, supervision of experiments, co-wrote the manuscript, and funding acquisition; B.E.—conceived project, study design, supervision of experiments, data analysis and interpretation, co-wrote the manuscript and funding acquisition. All authors critically evaluated the manuscript prior to submission.
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B.E. and H.E.G. are cofounders of Exavir Therapeutics, Inc. and are inventors on patents that cover ULA BIC formulations. The authors declare that this work was produced solely by the authors and that no other individuals or entities influenced any aspects of the work, including, but not limited to, the study conception and design, data acquisition, analyses, and interpretation, and writing of the manuscript. The authors further declare that they have received no financial compensation from any other third parties for any aspects of the published work. The remaining authors declare no competing interests.
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Nayan, M.U., Sillman, B., Das, S. et al. An ultra-long-acting dimeric bictegravir prodrug defined by a short pharmacokinetic tail. Nat Commun (2026). https://doi.org/10.1038/s41467-026-68501-5
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DOI: https://doi.org/10.1038/s41467-026-68501-5
