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Mechanistic insights into lenacapavir-induced off-pathway HIV-1 capsid assembly.

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Title: Mechanistic insights into lenacapavir-induced off-pathway HIV-1 capsid assembly.
Authors: Gupta, Manish1, Waltmann, Curt1, Renner, Nadine2, Wang, Yihang1, James, Leo C.2, Jacques, David A.3, Böcking, Till3, Voth, Gregory A.1 gavoth@uchicago.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 3/17/2026, Vol. 123 Issue 11, p1-11. 25p.
Subjects: Capsids, Antiviral agents, Chemical inhibitors, Molecular dynamics, Ribosomes, Inositol phosphates
Abstract: The HIV-1 capsid is a fullerene cone composed of hexameric and pentameric capsid proteins (CA) that packages the viral genome and mediates nuclear entry. Lenacapavir (LEN), a potent molecular long-acting inhibitor developed by Gilead, disrupts capsid morphogenesis by binding a phenylalanine-glycine (FG) pocket at the interface between adjacent CA subunits. Interestingly, cellular polyanion inositol hexakisphosphate (IP6) promotes conical capsid assembly by coordinating the central pore, which is allosterically coupled to the FG pocket. Because LEN and IP6 engage overlapping structural elements, they can compete to influence the capsid assembly pathway and outcomes. Using coarse-grained molecular simulations, we show that LEN accelerates hexamer formation while suppressing pentamer incorporation, yielding malformed, multilayered, and incomplete capsids. Simulations incorporating a ribonucleoprotein model further reveal that LEN-treated capsids often fail to encapsulate RNA, indicating impaired maturation. Our calculations confirm that LEN impairs the formation of high-curvature CA lattice regions necessary for closure, supporting a model of off-pathway assembly as a mechanism of viral inhibition. These findings define the core mechanism by which a small-molecule inhibitor disrupts the much larger-scale HIV-1 morphogenesis and underscore general principles for targeting self-assembling multi-protein complexes. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
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PubType: Academic Journal
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  Data: Mechanistic insights into lenacapavir-induced off-pathway HIV-1 capsid assembly.
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  Data: <searchLink fieldCode="AR" term="%22Gupta%2C+Manish%22">Gupta, Manish</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Waltmann%2C+Curt%22">Waltmann, Curt</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Renner%2C+Nadine%22">Renner, Nadine</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Wang%2C+Yihang%22">Wang, Yihang</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22James%2C+Leo+C%2E%22">James, Leo C.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Jacques%2C+David+A%2E%22">Jacques, David A.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Böcking%2C+Till%22">Böcking, Till</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Voth%2C+Gregory+A%2E%22">Voth, Gregory A.</searchLink><relatesTo>1</relatesTo><i> gavoth@uchicago.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 3/17/2026, Vol. 123 Issue 11, p1-11. 25p.
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  Data: <searchLink fieldCode="DE" term="%22Capsids%22">Capsids</searchLink><br /><searchLink fieldCode="DE" term="%22Antiviral+agents%22">Antiviral agents</searchLink><br /><searchLink fieldCode="DE" term="%22Chemical+inhibitors%22">Chemical inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+dynamics%22">Molecular dynamics</searchLink><br /><searchLink fieldCode="DE" term="%22Ribosomes%22">Ribosomes</searchLink><br /><searchLink fieldCode="DE" term="%22Inositol+phosphates%22">Inositol phosphates</searchLink>
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  Data: The HIV-1 capsid is a fullerene cone composed of hexameric and pentameric capsid proteins (CA) that packages the viral genome and mediates nuclear entry. Lenacapavir (LEN), a potent molecular long-acting inhibitor developed by Gilead, disrupts capsid morphogenesis by binding a phenylalanine-glycine (FG) pocket at the interface between adjacent CA subunits. Interestingly, cellular polyanion inositol hexakisphosphate (IP6) promotes conical capsid assembly by coordinating the central pore, which is allosterically coupled to the FG pocket. Because LEN and IP6 engage overlapping structural elements, they can compete to influence the capsid assembly pathway and outcomes. Using coarse-grained molecular simulations, we show that LEN accelerates hexamer formation while suppressing pentamer incorporation, yielding malformed, multilayered, and incomplete capsids. Simulations incorporating a ribonucleoprotein model further reveal that LEN-treated capsids often fail to encapsulate RNA, indicating impaired maturation. Our calculations confirm that LEN impairs the formation of high-curvature CA lattice regions necessary for closure, supporting a model of off-pathway assembly as a mechanism of viral inhibition. These findings define the core mechanism by which a small-molecule inhibitor disrupts the much larger-scale HIV-1 morphogenesis and underscore general principles for targeting self-assembling multi-protein complexes. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1073/pnas.2524995123
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      – SubjectFull: Antiviral agents
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      – SubjectFull: Chemical inhibitors
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      – SubjectFull: Molecular dynamics
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      – SubjectFull: Ribosomes
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      – SubjectFull: Inositol phosphates
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              Text: 3/17/2026
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              Y: 2026
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