دورية أكاديمية
أعرض في EDS

Structure-based identification and neutralization mechanism of tyrosine sulfate mimetics that inhibit HIV-1 entry.

التفاصيل البيبلوغرافية
العنوان: Structure-based identification and neutralization mechanism of tyrosine sulfate mimetics that inhibit HIV-1 entry.
المؤلفون: Acharya P; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States., Dogo-Isonagie C, LaLonde JM, Lam SN, Leslie GJ, Louder MK, Frye LL, Debnath AK, Greenwood JR, Luongo TS, Martin L, Watts KS, Hoxie JA, Mascola JR, Bewley CA, Kwong PD
المصدر: ACS chemical biology [ACS Chem Biol] 2011 Oct 21; Vol. 6 (10), pp. 1069-77. Date of Electronic Publication: 2011 Aug 05.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 101282906 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1554-8937 (Electronic) Linking ISSN: 15548929 NLM ISO Abbreviation: ACS Chem Biol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, D.C. : American Chemical Society, c2006-
مواضيع طبية MeSH: Anti-HIV Agents/*chemistry , Anti-HIV Agents/*pharmacology , HIV-1/*drug effects , Tyrosine/*analogs & derivatives , Virus Internalization/*drug effects, CD4 Antigens/immunology ; HIV Envelope Protein gp120/immunology ; HIV Envelope Protein gp120/metabolism ; HIV Infections/drug therapy ; HIV-1/physiology ; Humans ; Models, Molecular ; Tyrosine/chemistry ; Tyrosine/pharmacology
مستخلص: 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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معلومات مُعتمدة: R01 AI045378 United States AI NIAID NIH HHS; P01 GM056550 United States GM NIGMS NIH HHS; R37 AI045378 United States AI NIAID NIH HHS; GM 56550 United States GM NIGMS NIH HHS; ZIA AI005023-09 United States ImNIH Intramural NIH HHS
المشرفين على المادة: 0 (Anti-HIV Agents)
0 (CD4 Antigens)
0 (HIV Envelope Protein gp120)
29166358BF (tyrosine O-sulfate)
42HK56048U (Tyrosine)
تواريخ الأحداث: Date Created: 20110729 Date Completed: 20120216 Latest Revision: 20211020
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC3205951
DOI: 10.1021/cb200068b
PMID: 21793507
قاعدة البيانات: MEDLINE
الوصف
تدمد:1554-8937
DOI:10.1021/cb200068b