ArticleACS chemical biology2011
Structure-based identification and neutralization mechanism of tyrosine sulfate mimetics that inhibit HIV-1 entry.
Article in ACS chemical biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 32 citations in OpenAlex.
- Powerful Potential of Polyfluoroalkyl-Containing 4-Arylhydrazinylidenepyrazol-3-ones for Pharmaceuticals.Molecules (Basel, Switzerland) · 2022Article
- Development of a 3Mut-Apex-Stabilized Envelope Trimer That Expands HIV-1 Neutralization Breadth When Used To Boost Fusion Peptide-Directed Vaccine-Elicited Responses.Journal of virology · 2020Article
- Inhibitory Effects ofInternational journal of molecular sciences · 2019Article
- Advances in the Development of Shape Similarity Methods and Their Application in Drug Discovery.Frontiers in chemistry · 2018Review
- Investigating the geometrical preferences of a flexible benzimidazolone-based linker in the synthesis of coordination polymers.Royal Society open science · 2017Article
- Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome.Translational research : the journal of laboratory and clinical medicine · 2017Review
- Design and synthesis of small molecule-sulfotyrosine mimetics that inhibit HIV-1 entry.Bioorganic & medicinal chemistry · 2016Article
- Molecular mechanism of respiratory syncytial virus fusion inhibitors.Nature chemical biology · 2016Article
- Article
- HIV-1 gp120 as a therapeutic target: navigating a moving labyrinth.Expert opinion on therapeutic targets · 2015Review
- An extended CCR5 ECL2 peptide forms a helix that binds HIV-1 gp120 through non-specific hydrophobic interactions.The FEBS journal · 2015Article
- Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo.Nature communications · 2015Article
- Hierarchical virtual screening approaches in small molecule drug discovery.Methods (San Diego, Calif.) · 2015Review
- Template-constrained cyclic sulfopeptide HIV-1 entry inhibitors.Organic & biomolecular chemistry · 2013Article
- Heavy chain-only IgG2b llama antibody effects near-pan HIV-1 neutralization by recognizing a CD4-induced epitope that includes elements of coreceptor- and CD4-binding sites.Journal of virology · 2013Article
- Structural basis for highly effective HIV-1 neutralization by CD4-mimetic miniproteins revealed by 1.5 Å cocrystal structure of gp120 and M48U1.Structure (London, England : 1993) · 2013Article
- NMR mapping of RANTES surfaces interacting with CCR5 using linked extracellular domains.The FEBS journal · 2013Article
- HIV-1 Env gp120 structural determinants for peptide triazole dual receptor site antagonism.Proteins · 2013Article
- Peptides from second extracellular loop of C-C chemokine receptor type 5 (CCR5) inhibit diverse strains of HIV-1.The Journal of biological chemistry · 2012Article
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Authors and funding
16 authors at 6 institutions in 2 countries.
Funding
Abstract
Tyrosine sulfate-mediated interactions play an important role in HIV-1 entry. After engaging the CD4 receptor at the cell surface, the HIV-1 gp120 glycoprotein binds to the CCR5 co-receptor via an interaction that requires two tyrosine sulfates, at positions 10 and 14 in the CCR5-N terminus. Building on previous structure determinations of this interaction, here we report the targeting of these tyrosine sulfate binding sites for drug design through in silico screening of small molecule libraries, identification of lead compounds, and characterization of biological activity. A class of tyrosine sulfate-mimicking small molecules containing a "phenyl sulfonate-linker-aromatic" motif was identified that specifically inhibited binding of gp120 to the CCR5-N terminus as well as to sulfated antibodies that recognize the co-receptor binding region on gp120. The most potent of these compounds bound gp120 with low micromolar affinity and its CD4-induced conformation with K(D)'s as tight as ∼50 nM. Neutralization experiments suggested the targeted site to be conformationally inaccessible prior to CD4 engagement. Primary HIV-1 isolates were weakly neutralized, preincubation with soluble CD4 enhanced neutralization, and engineered isolates with increased dependence on the N terminus of CCR5 or with reduced conformational barriers were neutralized with IC(50) values as low as ∼1 μM. These results reveal the potential of targeting the tyrosine sulfate interactions of HIV-1 and provide insight into how mechanistic barriers, evolved by HIV-1 to evade antibody recognition, also restrict small-molecule-mediated neutralization.
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