Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein

Zvi Hayouka; Mattan Hurevich; Aviad Levin; Hadar Benyamini; Anat Iosub; Michal Maes; Deborah E. Shalev; Abraham Loyter; Chaim Gilon; Assaf Friedler

doi:10.1016/j.bmc.2010.09.046

Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein

Zvi Hayouka
, Mattan Hurevich
, Aviad Levin
, Hadar Benyamini
, Anat Iosub
, Michal Maes
, Deborah E. Shalev
, Abraham Loyter
, Chaim Gilon
, Assaf Friedler^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

52 Scopus citations

Abstract

Restricting linear peptides to their bioactive conformation is an attractive way of improving their stability and activity. We used a cyclic peptide library with conformational diversity for selecting an active and stable peptide that mimics the structure and activity of the HIV-1 integrase (IN) binding loop from its cellular cofactor LEDGF/p75 (residues 361-370). All peptides in the library had the same primary sequence, and differed only in their conformation. Library screening revealed that the ring size and linker structure had a huge effect on the conformation, binding and activity of the peptides. One of the cyclic peptides, c(MZ 4-1), was a potent and stable inhibitor of IN activity in vitro and in cells even after 8 days. The NMR structure of c(MZ 4-1) showed that it obtains a bioactive conformation that is similar to the parent site in LEDGF/p75.

Original language	English
Pages (from-to)	8388-8395
Number of pages	8
Journal	Bioorganic and Medicinal Chemistry
Volume	18
Issue number	23
DOIs	https://doi.org/10.1016/j.bmc.2010.09.046
State	Published - 1 Dec 2010

Bibliographical note

Funding Information:
A.F. is supported by a starting grant from the European Research Council under the European Community’s Seventh Framework Programme ( FP7/2007-2013 )/ERC Grant agreement n° 203413. A.L. is supported by the Israel Science Foundation (ISF; Grant No. 888/05 ). H.B is supported by a fellowship from the Israel Cancer research Foundation (ICRF). Some molecular graphics images were produced using the Chimera package from the University of California, San Francisco (supported by NIH P41 RR-01081).

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cyclic peptides
HIV-1
Intergase inhibitors
NMR
Protein mimetics
Protein-protein interactions

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10.1016/j.bmc.2010.09.046

Cite this

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title = "Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein",

abstract = "Restricting linear peptides to their bioactive conformation is an attractive way of improving their stability and activity. We used a cyclic peptide library with conformational diversity for selecting an active and stable peptide that mimics the structure and activity of the HIV-1 integrase (IN) binding loop from its cellular cofactor LEDGF/p75 (residues 361-370). All peptides in the library had the same primary sequence, and differed only in their conformation. Library screening revealed that the ring size and linker structure had a huge effect on the conformation, binding and activity of the peptides. One of the cyclic peptides, c(MZ 4-1), was a potent and stable inhibitor of IN activity in vitro and in cells even after 8 days. The NMR structure of c(MZ 4-1) showed that it obtains a bioactive conformation that is similar to the parent site in LEDGF/p75.",

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AU - Maes, Michal

AU - Shalev, Deborah E.

AU - Loyter, Abraham

AU - Gilon, Chaim

AU - Friedler, Assaf

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AB - Restricting linear peptides to their bioactive conformation is an attractive way of improving their stability and activity. We used a cyclic peptide library with conformational diversity for selecting an active and stable peptide that mimics the structure and activity of the HIV-1 integrase (IN) binding loop from its cellular cofactor LEDGF/p75 (residues 361-370). All peptides in the library had the same primary sequence, and differed only in their conformation. Library screening revealed that the ring size and linker structure had a huge effect on the conformation, binding and activity of the peptides. One of the cyclic peptides, c(MZ 4-1), was a potent and stable inhibitor of IN activity in vitro and in cells even after 8 days. The NMR structure of c(MZ 4-1) showed that it obtains a bioactive conformation that is similar to the parent site in LEDGF/p75.

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Cyclic peptide inhibitors of HIV-1 integrase derived from the LEDGF/p75 protein

Abstract

Bibliographical note

UN SDGs

Keywords

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