ArticlemBio2022
Structural and Mechanistic Bases of Viral Resistance to HIV-1 Capsid Inhibitor Lenacapavir.
Article in mBio, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed, 49 citations in OpenAlex.
- Capsid-Targeting Biologic Achieves Broad HIV-1 Neutralization with a High Barrier to Resistance.International journal of molecular sciences · 2026Article
- HIV capsid inhibitors: Mechanisms, resistance, and therapeutic advances.PLoS pathogens · 2026Review
- Mechanism of HIV-1 Capsid Rupture and Uncoating by Reverse Transcription.bioRxiv : the preprint server for biology · 2026Article
- Discovery of 4-Quinazolinone-Containing Phenylalanine Derivatives as Potent, Resistant-Tolerant HIV Capsid Inhibitors.MedComm · 2026Article
- Initiation of Long-Acting Antiretroviral Combinations Achieve Sustained Virologic Remission in Early-Life SIV Infection.Research square · 2026Article
- Mechanistic insights into lenacapavir-induced off-pathway HIV-1 capsid assembly.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Recurrent and novel evolutionary pathways drive in vitro HIV-1 lenacapavir resistance with diverse phenotypic consequences.Nature communications · 2026Article
- TARDBP as a regulator of HIV-1 assembly and infection: a review of targeting the viral capsid precursor Pr55Gag and limiting viral core entry.Cell communication and signaling : CCS · 2026Review
- Lenacapavir prevents production of infectious HIV-1 by abrogating immature virus assembly.bioRxiv : the preprint server for biology · 2026Article
- Toward Reconciling the Standard Binding Free Energy of Lenacapavir to HIV-1 Capsid with Experiment: Thermodynamic Effects of Solvent Buffer and Ligand Reorganization.The journal of physical chemistry. B · 2026Article
- Lenacapavir at the Spatiotemporal Limit: Tissue Pharmacokinetics, Pharmacokinetic Tail Dynamics, and the Emergence of Capsid Resistance in Long-Acting HIV Prevention.Clinical pharmacology : advances and applications · 2026Review
- HIV-1 and Its Strategy for Hiding Viral cDNA from STING-Mediated Innate Immunity.International journal of molecular sciences · 2025Review
- Distinct Target Site of Lenacapavir in Immature HIV-1 and Concurrent Binding with the Maturation Inhibitor Bevirimat.Journal of the American Chemical Society · 2025Article
- Delineating Structural Functionalities of Lenacapavir Amenable to Modifications for Targeting Emerging Drug-Resistant HIV‑1 Capsid Variants.ACS medicinal chemistry letters · 2025Article
- Lenacapavir-associated drug resistance: implications for scaling up long-acting HIV pre-exposure prophylaxis.The lancet. HIV · 2025Review
- Pharmacokinetics, pharmacodynamics, efficacy and drug resistance selection of injectable long-acting lenacapavir pre-exposure prophylaxis (PrEP) against HIV.medRxiv : the preprint server for health sciences · 2025Article
- Characterization of antiviral compounds using Bio-Layer Interferometry.bioRxiv : the preprint server for biology · 2025Article
- Understanding the HIV-CA protein and the ligands that bind at the N-terminal domain (NTD) - C-terminal domain (CTD) interface.RSC medicinal chemistry · 2025Review
- New Advances in Anti-HIV-1 Strategies Targeting the Assembly and Stability of Capsid Protein.International journal of molecular sciences · 2025Review
- Structural and mechanistic bases for resistance of the M66I capsid variant to lenacapavir.mBio · 2025Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Lenacapavir (LEN) is a long-acting, highly potent HIV-1 capsid (CA) inhibitor. The evolution of viral variants under the genetic pressure of LEN identified Q67H, N74D, and Q67H/N74D CA substitutions as the main resistance associated mutations (RAMs). Here, we determined high-resolution structures of CA hexamers containing these RAMs in the absence and presence of LEN. Our findings reveal that the Q67H change induces a conformational switch, which adversely affects the inhibitor binding. In the unliganded protein, the His67 side chain adopts the closed conformation by projecting into the inhibitor binding pocket and thereby creating steric hindrance with respect to LEN. Upon the inhibitor binding, the His67 side chain repositions to the open conformation that closely resembles the Gln67 side chain in the WT protein. We propose that the switch from the closed conformation to the open conformation, which is needed to accommodate LEN, accounts for the reduced inhibitor potency with respect to the Q67H CA variant. The N74D CA change results in the loss of a direct hydrogen bond and in induced electrostatic repulsions between CA and LEN. The double Q67H/N74D substitutions exhibited cumulative effects of respective single amino acid changes. An examination of LEN binding kinetics to CA hexamers revealed that Q67H and N74D CA changes adversely influenced the inhibitor binding affinity (
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.