The University of Southampton
University of Southampton Institutional Repository

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.

Text
Lennard at al manuscript - Accepted Manuscript
Download (4kB)

More information

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

Catalogue record

Date deposited: 28 Aug 2019 16:30
Last modified: 15 Sep 2021 04:24

Export record

Altmetrics

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×