ArticleProceedings of the National Academy of Sciences of the United States of America2007
Inhibiting HIV-1 integrase by shifting its oligomerization equilibrium.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 87 papers.
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87 citing papers in PubMed, 183 citations in OpenAlex.
- The Psu protein of phage satellite P4 inhibits transcription termination factor ρ by forced hyper-oligomerization.Nature communications · 2025Article
- Uncovering cell-type-specific immunomodulatory variants and molecular phenotypes in COVID-19 using structurally resolved protein networks.Cell reports · 2024Article
- Design of Vif-Derived Peptide Inhibitors with Anti-HIV-1 Activity by Interrupting Vif-CBFβ Interaction.Viruses · 2024Article
- Aptamers targeting SARS-CoV-2 nucleocapsid protein exhibit potential anti pan-coronavirus activity.Signal transduction and targeted therapy · 2024Article
- Designing Cyclic-Constrained Peptides to Inhibit Human Phosphoglycerate Dehydrogenase.Molecules (Basel, Switzerland) · 2023Article
- Serine-arginine protein kinases and their targets in viral infection and their inhibition.Cellular and molecular life sciences : CMLS · 2023Review
- A 3D structural SARS-CoV-2-human interactome to explore genetic and drug perturbations.Nature methods · 2021Article
- Review
- Tumor Necrosis Factor-α Trimer Disassembly and Inactivation via Peptide-Small Molecule Synergy.ACS chemical biology · 2020Article
- Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition.The Journal of biological chemistry · 2019Review
- Allostery in Its Many Disguises: From Theory to Applications.Structure (London, England : 1993) · 2019Review
- HIV-1 Integrase-Targeted Short Peptides Derived from a Viral Protein R Sequence.Molecules (Basel, Switzerland) · 2018Article
- Cellular and molecular mechanisms of HIV-1 integration targeting.Cellular and molecular life sciences : CMLS · 2018Review
- Retroviral intasomes arising.Current opinion in structural biology · 2017Review
- A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain.The Journal of biological chemistry · 2016Article
- The Preserved HTH-Docking Cleft of HIV-1 Integrase Is Functionally Critical.Structure (London, England : 1993) · 2016Article
- A novel assay for screening inhibitors targeting HIV-1 integrase dimerization based on Ni-NTA magnetic agarose beads.Scientific reports · 2016Article
- Recent insights into the development of therapeutics against coronavirus diseases by targeting N protein.Drug discovery today · 2016Review
- HIV-1 Gag as an Antiviral Target: Development of Assembly and Maturation Inhibitors.Current topics in medicinal chemistry · 2016Review
- Predicted binding site information improves model ranking in protein docking using experimental and computer-generated target structures.BMC structural biology · 2015Article
27 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proteins are involved in various equilibria that play a major role in their activity or regulation. The design of molecules that shift such equilibria is of great therapeutic potential. This fact was demonstrated in the cases of allosteric inhibitors, which shift the equilibrium between active and inactive (R and T) states, and chemical chaperones, which shift folding equilibrium of proteins. Here, we expand these concepts and propose the shifting of oligomerization equilibrium of proteins as a general methodology for drug design. We present a strategy for inhibiting proteins by "shiftides": ligands that specifically bind to an inactive oligomeric state of a disease-related protein and modulate its activity by shifting the oligomerization equilibrium of the protein toward it. We demonstrate the feasibility of our approach for the inhibition of the HIV-1 integrase (IN) protein by using peptides derived from its cellular-binding protein, LEDGF/p75, which specifically inhibit IN activity by a noncompetitive mechanism. The peptides inhibit the DNA-binding of IN by shifting the IN oligomerization equilibrium from the active dimer toward the inactive tetramer, which is unable to catalyze the first integration step of 3' end processing. The LEDGF/p75-derived peptides inhibit the enzymatic activity of IN in vitro and consequently block HIV-1 replication in cells because of the lack of integration. These peptides are promising anti-HIV lead compounds that modulate oligomerization of IN via a previously uncharacterized mechanism, which bears advantages over the conventional interface dimerization inhibitors.
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