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Development of a cyclic peptide inhibitor of the p6/UEV protein- protein interaction

Development of a cyclic peptide inhibitor of the p6/UEV protein- protein interaction
Development of a cyclic peptide inhibitor of the p6/UEV protein- protein interaction
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.
1554-8929
Lennard, Katherine
1ddd5215-8af1-4654-ac6e-f6ff308403da
Gardner, Reece
e09aff5b-e46b-4248-8f25-b7581d023b47
Doigneaux, Cyrielle
9f8adf0b-137e-4642-8cfc-e7e0e556d4b0
Castillo Correa, Francisco
e99a4b66-a412-4c99-a87d-f981d8769c67
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2
Lennard, Katherine
1ddd5215-8af1-4654-ac6e-f6ff308403da
Gardner, Reece
e09aff5b-e46b-4248-8f25-b7581d023b47
Doigneaux, Cyrielle
9f8adf0b-137e-4642-8cfc-e7e0e556d4b0
Castillo Correa, Francisco
e99a4b66-a412-4c99-a87d-f981d8769c67
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Lennard, Katherine, Gardner, Reece, Doigneaux, Cyrielle, Castillo Correa, Francisco and Tavassoli, Ali (2019) Development of a cyclic peptide inhibitor of the p6/UEV protein- protein interaction. ACS Chemical Biology. (doi:10.1021/acschembio.9b00627).

Record type: Article

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.

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Lennard at al manuscript - Accepted Manuscript
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Accepted/In Press date: 9 August 2019
e-pub ahead of print date: 14 August 2019

Identifiers

Local EPrints ID: 433612
URI: http://eprints.soton.ac.uk/id/eprint/433612
ISSN: 1554-8929
PURE UUID: 5bd62515-443e-4598-9166-c0a028acd79b
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

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Date deposited: 28 Aug 2019 16:30
Last modified: 16 Mar 2024 08:08

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Contributors

Author: Katherine Lennard
Author: Reece Gardner
Author: Cyrielle Doigneaux
Author: Francisco Castillo Correa
Author: Ali Tavassoli ORCID iD

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