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TitlePi-pi stacking interactions with viral DNA contribute to the potency of naphthyridine-based HIV-1 integrase inhibitors.
Journal, issue, pagesNAR Mol Med, Vol. 2, Issue 4, Page ugaf039, Year 2025
Publish dateNov 19, 2025
AuthorsXue Zhi Zhao / Min Li / Steven J Smith / Arvin Karbasi / Indrani Choudhuri / Tao Jing / Dmitry Lyumkis / Robert Craigie / Terrence R Burke /
PubMed AbstractDrug resistance remains a significant obstacle to identifying effective treatments for HIV-1 infection. Integrase strand transfer inhibitors (INSTIs) are frontline treatments used in combination ...Drug resistance remains a significant obstacle to identifying effective treatments for HIV-1 infection. Integrase strand transfer inhibitors (INSTIs) are frontline treatments used in combination antiretroviral therapy, but their efficacy can be compromised by emergence of resistance-associated mutations. The development of compounds that will retain efficacy against drug-resistant variants is of significant interest. Herein, we report the synthesis of naphthyridine-based INSTIs with a combination of 4-amino and 5-hydroxymethyl groups. Comparison of the resistance mutant profiles of the new compounds with FDA-approved second-generation INSTIs showed that the lead compounds are comparable to or surpass the efficacy of clinically used drugs against some of the most prevalent drug-resistant mutations that emerge in patient-derived viral isolates. High-resolution cryogenic electron microscopy (cryo-EM) structures of HIV-1 intasomes with two of the best naphthyridine-based INSTIs bound highlight how these inhibitors make enhanced interactions with viral DNA, particularly through optimized DNA stacking. Molecular dynamics simulations together with quantum mechanical and molecular mechanical calculations indicate that the interplay between intramolecular bonding, stacking geometry, resonance effects, and charge distribution governs drug binding within the active site of the intasome. The data mechanistically explain how key interactions contribute to improved antiviral potency against drug-resistant mutants and highlight a new strategy to combat HIV-1 resistance.
External linksNAR Mol Med / PubMed:41426354 / PubMed Central
MethodsEM (single particle)
Resolution2.28 - 2.33 Å
Structure data

72221

9q50

EMDB-72221, PDB-9q50:
AK01 integrase inhibitor bound to Wild-type HIV-1 intasome
Method: EM (single particle) / Resolution: 2.33 Å

72222

9q57

EMDB-72222, PDB-9q57:
XZ440 integrase inhibitor bound to Wild-type HIV-1 intasome
Method: EM (single particle) / Resolution: 2.28 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ZN:
Unknown entry

PDB-1cof:
YEAST COFILIN, ORTHORHOMBIC CRYSTAL FORM

ChemComp-HOH:
WATER

ChemComp-R7K:
~{N}-[[2,4-bis(fluoranyl)phenyl]methyl]-5-(hydroxymethyl)-1,4-bis(oxidanyl)-2-oxidanylidene-1,8-naphthyridine-3-carboxamide

Source
  • HIV type 1 (virus)
  • hiv-1 06tg.ht008 (virus)
KeywordsVIRAL PROTEIN/INHIBITOR/DNA / viral protein / protein complex / integrase inhibitor / VIRAL PROTEIN-INHIBITOR-DNA complex

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