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Peer-reviewedCC BY-NCScience Advances

Lenacapavir allosterically remodels the HIV-1 capsid

  • Nayara F. B. dos Santos1
  • Jacob A. Lewis1
  • Mason Hansen1
  • Miguel J. B. Pereira1
  • Devin E. Christensen1
  • Wesley I. Sundquist1
  • Barbie K. Ganser‐Pornillos1
  • Owen Pornillos1
  1. 1Department of Biochemistry, Spencer Fox Eccles School of Medicine, University of Utah, Salt Lake City, UT, USA
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Abstract

Lenacapavir (LEN) is a highly potent, long-acting HIV-1 capsid inhibitor that holds exceptional promise for pre-exposure prophylaxis. LEN causes the mature viral capsid to rupture and lose integrity, but the underlying mechanism has been unclear. Here, we show that LEN is an allosteric modulator of HIV-1 capsid structure that breaks the capsid's fullerene cone architecture in two steps: loss of high-curvature declinations occurs early, followed by failure of the capsid body. At the molecular level, LEN alters the non-covalent bonding interactions between capsid subunits and reduces local lattice curvature. LEN also alters the material properties of the capsid, by increasing brittleness. These results provide molecular rationales for how LEN remodels HIV-1 capsid structure and impairs the replication capacity of the virus.

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Cite

BibTeXRIS
BibTeX
@article{santos2026lenacapavir,
  title = {{Lenacapavir allosterically remodels the HIV-1 capsid}},
  author = {Nayara F. B. dos Santos and Jacob A. Lewis and Mason Hansen and Miguel J. B. Pereira and Devin E. Christensen and Wesley I. Sundquist and Barbie K. Ganser‐Pornillos and Owen Pornillos},
  journal = {Science Advances},
  year = {2026},
  month = sep,
  doi = {10.1126/sciadv.aed8384},
  url = {https://doi.org/10.1126/sciadv.aed8384},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Lenacapavir allosterically remodels the HIV-1 capsid
AU  - Nayara F. B. dos Santos
AU  - Jacob A. Lewis
AU  - Mason Hansen
AU  - Miguel J. B. Pereira
AU  - Devin E. Christensen
AU  - Wesley I. Sundquist
AU  - Barbie K. Ganser‐Pornillos
AU  - Owen Pornillos
PY  - 2026
DA  - 2026/09/02
JO  - Science Advances
DO  - 10.1126/sciadv.aed8384
UR  - https://doi.org/10.1126/sciadv.aed8384
AB  - Lenacapavir (LEN) is a highly potent, long-acting HIV-1 capsid inhibitor that holds exceptional promise for pre-exposure prophylaxis. LEN causes the mature viral capsid to rupture and lose integrity, but the underlying mechanism has been unclear. Here, we show that LEN is an allosteric modulator of HIV-1 capsid structure that breaks the capsid's fullerene cone architecture in two steps: loss of high-curvature declinations occurs early, followed by failure of the capsid body. At the molecular level, LEN alters the non-covalent bonding interactions between capsid subunits and reduces local lattice curvature. LEN also alters the material properties of the capsid, by increasing brittleness. These results provide molecular rationales for how LEN remodels HIV-1 capsid structure and impairs the replication capacity of the virus.
SN  - 2375-2548
ER  -