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HIV-1 Integrase Drug Discovery Comes of Age

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Therapy of Viral Infections

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 15))

Abstract

Insertion of the viral genome into host cell chromatin is a pivotal step in the replication cycle of the human immunodeficiency virus and other retroviruses. Blocking the viral integrase enzyme that catalyzes this reaction therefore provides an attractive therapeutic strategy. Nevertheless, many years lie between the initial discovery of integrase and the clinical approval of the first integrase strand transfer inhibitor, raltegravir, in 2007. Recently, elvitegravir was second to make it into the clinic, while dolutegravir, a second-generation integrase inhibitor, is close to receiving the green light as well. Viral resistance and cross-resistance among these strand transfer inhibitors however warrant the search for compounds targeting HIV integration through different mechanisms of action. The most advanced class of allosteric integrase inhibitors, coined LEDGINs or non-catalytic integrase inhibitors (NCINIs), has shown remarkable antiviral activity that extends beyond the viral integration step. Time will tell however if they will stand the test of clinical development. Notably, the development of LEDGINs and other integrase inhibitors is aided by recent structural and mechanistic insights into the retroviral integration apparatus. Here we provide an overview of the development of integrase strand transfer and allosteric inhibitors while exploring their mechanisms of action and patterns of viral resistance.

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Abbreviations

1-LTR:

1-Long terminal repeat

2-LTR:

2-Long terminal repeats

3P:

3′-Processing

ADME:

Absorption distribution, metabolism, and excretion

AIDS:

Acquired immunodeficiency syndrome

ALLINI:

Allosteric integrase inhibitor

ART:

Antiretroviral therapy

ARV:

Antiretroviral

CC50 :

50% cytotoxic concentration

CCD:

Catalytic core domain

CCR5:

C–C chemokine receptor 5

CR:

Charged region

CTD:

C-terminal domain

DKA:

Diketo acid

DNA:

Deoxyribonucleic acid

EC50 :

50% Effective concentration

FDA:

Food and Drug Administration

HAART:

Highly active antiretroviral therapy

HCV:

Hepatitis C virus

HDGF:

Hepatoma-derived growth factor

HIV-1:

Human immunodeficiency virus type 1

HIV-2:

Human immunodeficiency virus type 2

HRP-2:

Hepatoma-derived growth factor-related protein 2

HSAB:

Hard and soft Lewis acids and bases

IBD:

Integrase-binding domain

IC50 :

50% inhibitory concentration

IN:

Integrase

INI:

Integrase inhibitor

IRBM:

Instituto di Ricerche di Biologia Moleculare

LEDGF/p75:

Lens epithelium-derived growth factor/p75

LTR:

Long terminal repeat

MACCS:

Molecular access system

mRNA:

Messenger ribonucleic acid

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NCINI:

Non-catalytic site integrase inhibitor

NLS:

Nuclear localization signal

NMR:

Nuclear magnetic resonance

NNRTI:

Non-nucleoside reverse transcriptase inhibitor

NRTI:

Nucleoside reverse transcriptase inhibitor

NTD:

N-terminal domain

PAEC50 :

Protein-adjusted 50% effective concentration

PAIC50 :

Protein-adjusted 50% inhibitory concentration

PFV:

Prototype foamy virus

PHAT:

Pseudo-HEAT analogous topology

PIC:

Pre-integration complex

PK:

Pharmacokinetic

PPI:

Protein–protein interaction

PR:

Protease

PrEP:

Preexposure prophylaxis

PWWP:

Pro–Trp–Trp–Pro domain

RNA:

Ribonucleic acid

RT:

Reverse transcriptase

SAR:

Structure–activity relationship

SIV:

Simian immunodeficiency virus

SPR:

Surface plasmon resonance

ST:

Strand transfer

STD-NMR:

Saturation transfer difference nuclear magnetic resonance

tDNA:

Target deoxyribonucleic acid

TRN-SR2:

Transportin-SR2

vDNA:

Viral deoxyribonucleic acid

WT:

Wild type

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Authors and Affiliations

  1. Laboratory for Molecular Virology and Gene Therapy, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, Leuven, Belgium

    Jonas Demeulemeester & Zeger Debyser

  2. Laboratory for Biomolecular Modeling, Department of Chemistry, University of Leuven, Leuven, Belgium

    Jonas Demeulemeester & Marc De Maeyer

Authors
  1. Jonas Demeulemeester
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  2. Marc De Maeyer
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  3. Zeger Debyser
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Correspondence to Jonas Demeulemeester .

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Editors and Affiliations

  1. Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Marburg, Germany

    Wibke E. Diederich

  2. -, Bayer Pharma AG, Lead Discovery Berlin - Structural Biology, Berlin, Germany

    Holger Steuber

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Demeulemeester, J., De Maeyer, M., Debyser, Z. (2013). HIV-1 Integrase Drug Discovery Comes of Age. In: Diederich, W., Steuber, H. (eds) Therapy of Viral Infections. Topics in Medicinal Chemistry, vol 15. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7355_2013_33

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