Design and synthesis of small molecule-sulfotyrosine mimetics that inhibit HIV-1 entry
| Autor: | Katheryn Lohith, Cajetan Dogo-Isonagie, Robert D. O’Connor, Carole A. Bewley, Sivakoteswara Rao Mandadapu, Hong-Bing Liu, Su Lin Lee, Sabrina Lusvarghi |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Stereochemistry Clinical Biochemistry Pharmaceutical Science Peptide HIV Infections Microbial Sensitivity Tests HIV Envelope Protein gp120 Biochemistry Molecular Docking Simulation Article 03 medical and health sciences Structure-Activity Relationship Non-competitive inhibition Sulfation Biomimetic Materials Drug Discovery Structure–activity relationship Molecular Biology Infectivity chemistry.chemical_classification biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry virus diseases Virus Internalization Envelope glycoprotein GP120 Small molecule Molecular Weight 030104 developmental biology Drug Design biology.protein HIV-1 Molecular Medicine Tyrosine |
| Zdroj: | Bioorg Med Chem |
| ISSN: | 1464-3391 |
| Popis: | In the absence of a cure or vaccine for HIV/AIDS, small molecule inhibitors remain an attractive choice for antiviral therapeutics. Recent structural and functional studies of the HIV-1 surface envelope glycoprotein gp120 have revealed sites of vulnerability that can be targeted by small molecule and peptide inhibitors, thereby inhibiting HIV-1 infection. Here we describe a series of small molecule entry inhibitors that were designed to mimic the sulfated N-terminal peptide of the HIV-1 coreceptor CCR5. From a panel of hydrazonothiazolyl pyrazolinones, we demonstrate that compounds containing naphthyl di- and tri-sulfonic acids inhibit HIV-1 infection in single round infectivity assays with the disulfonic acids being the most potent. Molecular docking supports the observed structure activity relationship, and SPR confirmed binding to gp120. In infectivity assays treatment with a representative naphthyl disulfonate and a disulfated CCR5 N-terminus peptide results in competitive inhibition, with combination indices >2. In total this work shows that gp120 and HIV-1 infection can be inhibited by small molecules that mimic the function of, and are competitive with the natural sulfated CCR5 N-terminus. |
| Databáze: | OpenAIRE |
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