Abstract
The budding of HIV from infected cells is driven by the protein-protein interaction between the p6 domain of the HIV Gag protein and the UEV domain of the human TSG101 protein. We report the development of a cyclic peptide inhibitor of the p6/UEV interaction, from a non cell-permeable parent that was identified in a SICLOPPS screen. Amino acids critical for the activity of the parent cyclic peptide were uncovered using alanine-scanning, and a series of non-natural analogues synthesized and assessed. The most potent molecule disrupts the p6/UEV interaction with an IC50 of 6.17 ± 0.24 μM by binding to UEV with a Kd of 11.9 ± 2.8 μM. This compound is cell permeable and active in a cellular virus-like particle budding assay with an IC50 of ∼2 μM. This work further demonstrates the relative simplicity with which the potency and activity of cyclic peptides identified from SICLOPPS libraries can be optimized.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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DNA-Binding Proteins / chemistry
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism*
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Drug Development
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Endosomal Sorting Complexes Required for Transport / chemistry
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Endosomal Sorting Complexes Required for Transport / genetics
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Endosomal Sorting Complexes Required for Transport / metabolism*
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Escherichia coli / genetics
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HEK293 Cells
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HIV / chemistry
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HIV / drug effects
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HeLa Cells
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Humans
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Peptides, Cyclic / pharmacology*
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Peptides, Cyclic / toxicity
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Protein Binding / drug effects*
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Protein Domains
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Transcription Factors / chemistry
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Virus Release / drug effects
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gag Gene Products, Human Immunodeficiency Virus / metabolism*
Substances
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DNA-Binding Proteins
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Endosomal Sorting Complexes Required for Transport
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Peptides, Cyclic
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Transcription Factors
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Tsg101 protein
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gag Gene Products, Human Immunodeficiency Virus
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p6 gag protein, Human immunodeficiency virus 1