A new class of allosteric HIV-1 integrase inhibitors identified by crystallographic fragment screening of the catalytic core domain

Disha Patel, Janet Antwi, Pratibha C. Koneru, Erik Serrao, Stefano Forli, Jacques J. Kessl, Lei Feng, Nanjie Deng, Ronald M. Levy, James R. Fuchs, Arthur J. Olson, Alan N. Engelman, Joseph D. Bauman, Mamuka Kvaratskhelia, Eddy Arnold

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

HIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors. Using crystallographic screening of a library of 971 fragments against the HIV-1 IN catalytic core domain (CCD) followed by a fragment expansion approach, we have identified thiophenecarboxylic acid derivatives that bind at the CCD-CCD dimer interface at the principal lens epithelium-derived growth factor (LEDGF)/p75 binding pocket. The most active derivative (5) inhibited LEDGF/p75-dependent HIV-1 IN activity in vitro with an IC50 of 72 μM and impaired HIV-1 infection of T cells at an EC50 of 36 μM. The identified lead compound, with a relatively small molecular weight (221 Da), provides an optimal building block for developing a new class of inhibitors. Furthermore, although structurally distinct thiophenecarboxylic acid derivatives target a similar pocket at the IN dimer interface as the quinoline-based ALLINIs, the lead compound, 5, inhibited IN mutants that confer resistance to quinoline-based compounds. Collectively, our findings provide a plausible path for structurebased development of second-generation ALLINIs.

Original languageEnglish (US)
Pages (from-to)23569-23577
Number of pages9
JournalJournal of Biological Chemistry
Volume291
Issue number45
DOIs
StatePublished - Nov 4 2016

Fingerprint

HIV Integrase Inhibitors
Integrase Inhibitors
Integrases
Catalytic Domain
Screening
Lead compounds
Derivatives
Dimers
HIV-1
Acids
HIV Infections
T-cells
Viruses
Molecular Evolution
Molecular weight
Virus Replication
Morphogenesis
Virion
Inhibitory Concentration 50
Libraries

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Patel, Disha ; Antwi, Janet ; Koneru, Pratibha C. ; Serrao, Erik ; Forli, Stefano ; Kessl, Jacques J. ; Feng, Lei ; Deng, Nanjie ; Levy, Ronald M. ; Fuchs, James R. ; Olson, Arthur J. ; Engelman, Alan N. ; Bauman, Joseph D. ; Kvaratskhelia, Mamuka ; Arnold, Eddy. / A new class of allosteric HIV-1 integrase inhibitors identified by crystallographic fragment screening of the catalytic core domain. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 45. pp. 23569-23577.
@article{86652feb2d96430abd28888ef6c1c449,
title = "A new class of allosteric HIV-1 integrase inhibitors identified by crystallographic fragment screening of the catalytic core domain",
abstract = "HIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors. Using crystallographic screening of a library of 971 fragments against the HIV-1 IN catalytic core domain (CCD) followed by a fragment expansion approach, we have identified thiophenecarboxylic acid derivatives that bind at the CCD-CCD dimer interface at the principal lens epithelium-derived growth factor (LEDGF)/p75 binding pocket. The most active derivative (5) inhibited LEDGF/p75-dependent HIV-1 IN activity in vitro with an IC50 of 72 μM and impaired HIV-1 infection of T cells at an EC50 of 36 μM. The identified lead compound, with a relatively small molecular weight (221 Da), provides an optimal building block for developing a new class of inhibitors. Furthermore, although structurally distinct thiophenecarboxylic acid derivatives target a similar pocket at the IN dimer interface as the quinoline-based ALLINIs, the lead compound, 5, inhibited IN mutants that confer resistance to quinoline-based compounds. Collectively, our findings provide a plausible path for structurebased development of second-generation ALLINIs.",
author = "Disha Patel and Janet Antwi and Koneru, {Pratibha C.} and Erik Serrao and Stefano Forli and Kessl, {Jacques J.} and Lei Feng and Nanjie Deng and Levy, {Ronald M.} and Fuchs, {James R.} and Olson, {Arthur J.} and Engelman, {Alan N.} and Bauman, {Joseph D.} and Mamuka Kvaratskhelia and Eddy Arnold",
year = "2016",
month = "11",
day = "4",
doi = "10.1074/jbc.M116.753384",
language = "English (US)",
volume = "291",
pages = "23569--23577",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "45",

}

Patel, D, Antwi, J, Koneru, PC, Serrao, E, Forli, S, Kessl, JJ, Feng, L, Deng, N, Levy, RM, Fuchs, JR, Olson, AJ, Engelman, AN, Bauman, JD, Kvaratskhelia, M & Arnold, E 2016, 'A new class of allosteric HIV-1 integrase inhibitors identified by crystallographic fragment screening of the catalytic core domain', Journal of Biological Chemistry, vol. 291, no. 45, pp. 23569-23577. https://doi.org/10.1074/jbc.M116.753384

A new class of allosteric HIV-1 integrase inhibitors identified by crystallographic fragment screening of the catalytic core domain. / Patel, Disha; Antwi, Janet; Koneru, Pratibha C.; Serrao, Erik; Forli, Stefano; Kessl, Jacques J.; Feng, Lei; Deng, Nanjie; Levy, Ronald M.; Fuchs, James R.; Olson, Arthur J.; Engelman, Alan N.; Bauman, Joseph D.; Kvaratskhelia, Mamuka; Arnold, Eddy.

In: Journal of Biological Chemistry, Vol. 291, No. 45, 04.11.2016, p. 23569-23577.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A new class of allosteric HIV-1 integrase inhibitors identified by crystallographic fragment screening of the catalytic core domain

AU - Patel, Disha

AU - Antwi, Janet

AU - Koneru, Pratibha C.

AU - Serrao, Erik

AU - Forli, Stefano

AU - Kessl, Jacques J.

AU - Feng, Lei

AU - Deng, Nanjie

AU - Levy, Ronald M.

AU - Fuchs, James R.

AU - Olson, Arthur J.

AU - Engelman, Alan N.

AU - Bauman, Joseph D.

AU - Kvaratskhelia, Mamuka

AU - Arnold, Eddy

PY - 2016/11/4

Y1 - 2016/11/4

N2 - HIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors. Using crystallographic screening of a library of 971 fragments against the HIV-1 IN catalytic core domain (CCD) followed by a fragment expansion approach, we have identified thiophenecarboxylic acid derivatives that bind at the CCD-CCD dimer interface at the principal lens epithelium-derived growth factor (LEDGF)/p75 binding pocket. The most active derivative (5) inhibited LEDGF/p75-dependent HIV-1 IN activity in vitro with an IC50 of 72 μM and impaired HIV-1 infection of T cells at an EC50 of 36 μM. The identified lead compound, with a relatively small molecular weight (221 Da), provides an optimal building block for developing a new class of inhibitors. Furthermore, although structurally distinct thiophenecarboxylic acid derivatives target a similar pocket at the IN dimer interface as the quinoline-based ALLINIs, the lead compound, 5, inhibited IN mutants that confer resistance to quinoline-based compounds. Collectively, our findings provide a plausible path for structurebased development of second-generation ALLINIs.

AB - HIV-1 integrase (IN) is essential for virus replication and represents an important multifunctional therapeutic target. Recently discovered quinoline-based allosteric IN inhibitors (ALLINIs) potently impair HIV-1 replication and are currently in clinical trials. ALLINIs exhibit a multimodal mechanism of action by inducing aberrant IN multimerization during virion morphogenesis and by competing with IN for binding to its cognate cellular cofactor LEDGF/p75 during early steps of HIV-1 infection. However, quinoline-based ALLINIs impose a low genetic barrier for the evolution of resistant phenotypes, which highlights a need for discovery of second-generation inhibitors. Using crystallographic screening of a library of 971 fragments against the HIV-1 IN catalytic core domain (CCD) followed by a fragment expansion approach, we have identified thiophenecarboxylic acid derivatives that bind at the CCD-CCD dimer interface at the principal lens epithelium-derived growth factor (LEDGF)/p75 binding pocket. The most active derivative (5) inhibited LEDGF/p75-dependent HIV-1 IN activity in vitro with an IC50 of 72 μM and impaired HIV-1 infection of T cells at an EC50 of 36 μM. The identified lead compound, with a relatively small molecular weight (221 Da), provides an optimal building block for developing a new class of inhibitors. Furthermore, although structurally distinct thiophenecarboxylic acid derivatives target a similar pocket at the IN dimer interface as the quinoline-based ALLINIs, the lead compound, 5, inhibited IN mutants that confer resistance to quinoline-based compounds. Collectively, our findings provide a plausible path for structurebased development of second-generation ALLINIs.

UR - http://www.scopus.com/inward/record.url?scp=84994257527&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84994257527&partnerID=8YFLogxK

U2 - 10.1074/jbc.M116.753384

DO - 10.1074/jbc.M116.753384

M3 - Article

C2 - 27645997

AN - SCOPUS:84994257527

VL - 291

SP - 23569

EP - 23577

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 45

ER -