Application of an NMR/Crystallography Fragment Screening Platform for the Assessment and Rapid Discovery of New HIV-CA Binding Fragments

Stuart Lang; Daniel A. Fletcher; Alain-Pierre Petit; Nicola Luise; Paul Fyfe; Fabio Zuccotto; David Porter; Anthony Hope; Fiona Bellany; Catrina Kerr; Claire J. Mackenzie; Paul G. Wyatt; David W. Gray

doi:10.1002/cmdc.202400025

Application of an NMR/Crystallography Fragment Screening Platform for the Assessment and Rapid Discovery of New HIV-CA Binding Fragments

Stuart Lang
, Daniel A. Fletcher
, Alain-Pierre Petit
, Nicola Luise
, Paul Fyfe
, Fabio Zuccotto
, David Porter
, Anthony Hope
, Fiona Bellany
, Catrina Kerr
, Claire J. Mackenzie
, Paul G. Wyatt
, David W. Gray (Lead / Corresponding author)

Drug Discovery Unit

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

1 Citation (Scopus)

115 Downloads (Pure)

Abstract

Identification and assessment of novel targets is essential to combat drug resistance in the treatment of HIV/AIDS. HIV Capsid (HIV-CA), the protein playing a major role in both the early and late stages of the viral life cycle, has emerged as an important target. We have applied an NMR fragment screening platform and identified molecules that bind to the N-terminal domain (NTD) of HIV-CA at a site close to the interface with the C-terminal domain (CTD). Using X-ray crystallography, we have been able to obtain crystal structures to identify the binding mode of these compounds. This allowed for rapid progression of the initial, weak binding, fragment starting points to compounds 37 and 38, which have 19F-pKi values of 5.3 and 5.4 respectively.

Original language	English
Article number	e202400025
Number of pages	12
Journal	ChemMedChem
Volume	19
Issue number	13
Early online date	6 May 2024
DOIs	https://doi.org/10.1002/cmdc.202400025
Publication status	Published - 2 Jul 2024

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SDG 3 Good Health and Well-being

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10.1002/cmdc.202400025Licence: CC BY

Final published versionFinal published version, 3.3 MBLicence: CC BY

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Lang, S., Fletcher, D. A., Petit, A.-P., Luise, N., Fyfe, P., Zuccotto, F., Porter, D., Hope, A., Bellany, F., Kerr, C., Mackenzie, C. J., Wyatt, P. G., & Gray, D. W. (2024). Application of an NMR/Crystallography Fragment Screening Platform for the Assessment and Rapid Discovery of New HIV-CA Binding Fragments. ChemMedChem, 19(13), Article e202400025. https://doi.org/10.1002/cmdc.202400025

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title = "Application of an NMR/Crystallography Fragment Screening Platform for the Assessment and Rapid Discovery of New HIV-CA Binding Fragments",

abstract = "Identification and assessment of novel targets is essential to combat drug resistance in the treatment of HIV/AIDS. HIV Capsid (HIV-CA), the protein playing a major role in both the early and late stages of the viral life cycle, has emerged as an important target. We have applied an NMR fragment screening platform and identified molecules that bind to the N-terminal domain (NTD) of HIV-CA at a site close to the interface with the C-terminal domain (CTD). Using X-ray crystallography, we have been able to obtain crystal structures to identify the binding mode of these compounds. This allowed for rapid progression of the initial, weak binding, fragment starting points to compounds 37 and 38, which have 19F-pKi values of 5.3 and 5.4 respectively.",

author = "Stuart Lang and Fletcher, \{Daniel A.\} and Alain-Pierre Petit and Nicola Luise and Paul Fyfe and Fabio Zuccotto and David Porter and Anthony Hope and Fiona Bellany and Catrina Kerr and Mackenzie, \{Claire J.\} and Wyatt, \{Paul G.\} and Gray, \{David W.\}",

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doi = "10.1002/cmdc.202400025",

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Lang, S, Fletcher, DA, Petit, A-P, Luise, N, Fyfe, P, Zuccotto, F, Porter, D, Hope, A, Bellany, F , Kerr, C, Mackenzie, CJ, Wyatt, PG & Gray, DW 2024, 'Application of an NMR/Crystallography Fragment Screening Platform for the Assessment and Rapid Discovery of New HIV-CA Binding Fragments', ChemMedChem, vol. 19, no. 13, e202400025. https://doi.org/10.1002/cmdc.202400025

TY - JOUR

T1 - Application of an NMR/Crystallography Fragment Screening Platform for the Assessment and Rapid Discovery of New HIV-CA Binding Fragments

AU - Lang, Stuart

AU - Fletcher, Daniel A.

AU - Petit, Alain-Pierre

AU - Luise, Nicola

AU - Fyfe, Paul

AU - Zuccotto, Fabio

AU - Porter, David

AU - Hope, Anthony

AU - Bellany, Fiona

AU - Kerr, Catrina

AU - Mackenzie, Claire J.

AU - Wyatt, Paul G.

AU - Gray, David W.

PY - 2024/7/2

Y1 - 2024/7/2

N2 - Identification and assessment of novel targets is essential to combat drug resistance in the treatment of HIV/AIDS. HIV Capsid (HIV-CA), the protein playing a major role in both the early and late stages of the viral life cycle, has emerged as an important target. We have applied an NMR fragment screening platform and identified molecules that bind to the N-terminal domain (NTD) of HIV-CA at a site close to the interface with the C-terminal domain (CTD). Using X-ray crystallography, we have been able to obtain crystal structures to identify the binding mode of these compounds. This allowed for rapid progression of the initial, weak binding, fragment starting points to compounds 37 and 38, which have 19F-pKi values of 5.3 and 5.4 respectively.

AB - Identification and assessment of novel targets is essential to combat drug resistance in the treatment of HIV/AIDS. HIV Capsid (HIV-CA), the protein playing a major role in both the early and late stages of the viral life cycle, has emerged as an important target. We have applied an NMR fragment screening platform and identified molecules that bind to the N-terminal domain (NTD) of HIV-CA at a site close to the interface with the C-terminal domain (CTD). Using X-ray crystallography, we have been able to obtain crystal structures to identify the binding mode of these compounds. This allowed for rapid progression of the initial, weak binding, fragment starting points to compounds 37 and 38, which have 19F-pKi values of 5.3 and 5.4 respectively.

UR - https://www.scopus.com/pages/publications/85192157203

U2 - 10.1002/cmdc.202400025

DO - 10.1002/cmdc.202400025

M3 - Article

C2 - 38581280

SN - 1860-7179

VL - 19

JO - ChemMedChem

JF - ChemMedChem

IS - 13

M1 - e202400025

ER -

Application of an NMR/Crystallography Fragment Screening Platform for the Assessment and Rapid Discovery of New HIV-CA Binding Fragments

Abstract

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