Structure-Based Identification and Neutralization Mechanism of Tyrosine Sulfate Mimetics That Inhibit HIV-1 Entry
| Autor: | Jeremy R. Greenwood, George J. Leslie, Mark K. Louder, Carole A. Bewley, Leah L. Frye, Timothy S. Luongo, Cajetan Dogo-Isonagie, Priyamvada Acharya, Loïc Martin, Son N. Lam, K. Shawn Watts, Asim K. Debnath, Peter D. Kwong, John R. Mascola, Judith M. LaLonde, James A. Hoxie |
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| Přispěvatelé: | Vaccine Research Center, NIAID, National Institutes of Health, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA) |
| Rok vydání: | 2011 |
| Předmět: |
Models
Molecular Anti-HIV Agents viruses HIV Infections [CHIM.THER]Chemical Sciences/Medicinal Chemistry HIV Envelope Protein gp120 Biology Biochemistry Article Receptor tyrosine kinase 03 medical and health sciences 0302 clinical medicine Sulfation [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication [CHIM.CRIS]Chemical Sciences/Cristallography Humans [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Binding site Tyrosine ComputingMilieux_MISCELLANEOUS 030304 developmental biology chemistry.chemical_classification 0303 health sciences [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Structural Biology [q-bio.BM] virus diseases Small Molecule Libraries Biological activity General Medicine Virus Internalization Small molecule [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] 3. Good health [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] chemistry 030220 oncology & carcinogenesis CD4 Antigens HIV-1 biology.protein Molecular Medicine Glycoprotein |
| Zdroj: | ACS Chemical Biology ACS Chemical Biology, 2011, 6 (10), pp.1069-1077. ⟨10.1021/cb200068b⟩ ACS Chemical Biology, American Chemical Society, 2011, 6 (10), pp.1069-1077. ⟨10.1021/cb200068b⟩ |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/cb200068b |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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