HIV-1 Integrase Drug Discovery Comes of Age

Demeulemeester, Jonas; Maeyer, Marc De; Debyser, Zeger

doi:10.1007/7355_2013_33

Cited by 5 publications

(3 citation statements)

References 179 publications

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“…In a later study, the feasibility of this concept was indeed proven by designing and developing LEDGINs, first-in-class small molecule inhibitors binding to the LEDGF/p75 binding pocket of HIV-1 IN and potently blocking HIV replication [14,139]. A detailed review of the drug development will be provided in Demeulemeester et al [140].…”

Section: The Tertiary Structure Of Ledgf/p75mentioning

confidence: 97%

Targeting Cellular Cofactors in HIV Therapy

Dürr

Keppler

Christ

et al. 2014

Topics in Medicinal Chemistry

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Besides viral proteins cellular factors play a key role in the replication of the human immunodeficiency virus HIV-1. The outcome of virus replication is determined by the balance between the activity of a number of cellular dependency factors and restriction factors. Whereas the first are essential cofactors for diverse steps in the viral replication cycle, the latter counteract virus replication by sensing particular viral components as non-self, often as mediators of the innate immune system. Cellular cofactors include receptors for HIV-1 entry, LEDGF as cofactor for the viral integrase, the RNA helicase DDX3 involved in the nuclear export of unspliced viral RNAs, and diverse cellular kinases that promote viral replication. Cellular restriction factors are often antagonized by HIV-1 accessory proteins in order to counteract their restrictive function on viral replication. Although cellular cofactors in the HIV field are understood as factors promoting viral replication, we add a subchapter on the most important restriction factors (Trim5α, APOBEC3G, SAMHD1, and tetherin/BST-2). Today highly active antiretroviral therapy (HAART) mostly targets HIV proteins like reverse transcriptase, protease, or integrase to specifically interfere with virus replication. However, the identification of cellular cofactors and the increasing knowledge on their mode of action at R. Dürr and U. Dietrich (*) Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, Paul-Ehrlich-Str. 42-44, 60596 Frankfurt, Germany e-mail: duerr@gsh.uni-frankfurt.de; ursula.dietrich@gsh.uni-frankfurt.de O. Keppler Institute of Medical Virology, Goethe University, Frankfurt, Germany e-mail: oliver.keppler@kgu.de F. Christ Laboratory for Molecular Virology and Gene Therapy, K.U. Leuven, Leuven, Belgium e-mail: frauke.christ@med.kuleuven.be E. Crespan, A. Garbelli, and G. Maga Institute of Molecular Genetics, IGM-CNR, Pavia, Italy e-mail: emmanuelecrespan@gmail.com; agarbelli@gmail.com; maga@igm.cnr.it defined steps in the HIV-1 replication cycle have opened new avenues towards the development of HIV-1 inhibitors. Here we summarize the most important cellular factors involved in HIV-1 replication along with therapeutic approaches developed to target them, preferentially without harming their normal cellular function.

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Section: The Tertiary Structure Of Ledgf/p75mentioning

confidence: 97%

Targeting Cellular Cofactors in HIV Therapy

Dürr

Keppler

Christ

et al. 2014

Topics in Medicinal Chemistry

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“… 76 Zidovudine, the first antiretroviral designated to treat HIV, achieved FDA approval in 1986. 77 Although early retroviral therapy for HIV was not widely effective, 69 it remains impressive that in less than 6 years international research effort had lead to the recognition and characterization of AIDS, the isolation of the causative retrovirus, and the ability to offer treatment. The rapid advancements made in AIDS research owe much to the previous knowledge gained through the isolation of HTLV-1 and HTLV-II.…”

Section: Impact Of Ebv and Htlv-1mentioning

confidence: 99%

Viral Causes of Lymphoma: The History of Epstein-Barr Virus and Human T-Lymphotropic Virus 1

Esau

2017

Virology�(Auckl)

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In 1964, Epstein, Barr, and Achong published a report outlining their discovery of viral particles in lymphoblasts isolated from a patient with Burkitt lymphoma. The Epstein-Barr virus (EBV) was the first human cancer virus to be described, and its discovery paved the way for further investigations into the oncogenic potential of viruses. In the decades following the discovery of EBV, multinational research efforts led to the discovery of further viral causes of various human cancers. Lymphomas are perhaps the cancer type that is most closely associated with oncogenic viruses: infection with EBV, human T-lymphotropic virus 1 (HTLV-1), human immunodeficiency virus (HIV), Kaposi sarcoma-associated herpesvirus/human herpesvirus 8, and hepatitis C virus have all been associated with lymphomagenesis. Lymphomas have also played an important role in the history of oncoviruses, as both the first human oncovirus (EBV) and the first human retrovirus (HTLV-1) were discovered through isolates taken from patients with unique lymphoma syndromes. The history of the discovery of these 2 key oncoviruses is presented here, and their impact on further medical research, using the specific example of HIV research, is briefly discussed.

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“…Active site-targeted integrase strand transfer inhibitors (INSTIs) are clinically useful therapeutics that include raltegravir, elvitegravir, dolutegravir, and bictegravir (Figure ). These inhibitors bind to the active site of the integrase enzyme, forming a ternary complex with 3′ processed proviral DNA that impairs strand transfer activity, the step that initiates the integration of viral DNA into host DNA. In contrast, the allosteric integrase inhibitors (ALLINIs) bind to a site located at the HIV-1 integrase dimer interface that is recognized by the host cell transcription factor lens epithelium-derived growth factor (LEDGF/p75). − The important role of LEDGF/p75 in HIV-1 integration has been validated in vitro by site-directed mutagenesis studies, , RNAi knockdown experiments, and cellular expression of the integrase binding domain (IBD) of LEDGF that inhibits HIV-1 replication in cell culture. , Recent studies showed that the multifunctional ALLINIs not only inhibit IN binding to its cofactor LEDGF/p75 but also promote aberrant IN multimerization to block viral maturation, leading to the production of structurally defective, noninfectious virions. − The pleiotropic effects of ALLINIs suggest considerable promise as antiviral agents for the development of HIV-1 therapeutics .…”

Section: Introductionmentioning

confidence: 99%

Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors

et al. 2020

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The standard of care for HIV-1 infection, highly active antiretroviral therapy (HAART), combines two or more drugs from at least two classes. Even with the success of HAART, new drugs with novel mechanisms are needed to combat viral resistance, improve adherence, and mitigate toxicities. Active site inhibitors of HIV-1 integrase are clinically validated for the treatment of HIV-1 infection.Here we describe allosteric inhibitors of HIV-1 integrase that bind to the LEDGF/p75 interaction site and disrupt the structure of the integrase multimer that is required for the HIV-1 maturation. A series of pyrazolopyrimidine-based inhibitors was developed with a vector in the 2-position that was optimized by structure-guided compound design. This resulted in the discovery of pyrazolopyrimidine 3, which was optimized at the 2-and 7-positions to afford 26 and 29 as potent allosteric inhibitors of HIV-1 integrase that exhibited low nanomolar antiviral potency in cell culture and encouraging PK properties.

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HIV-1 Integrase Drug Discovery Comes of Age

Cited by 5 publications

References 179 publications

Targeting Cellular Cofactors in HIV Therapy

Targeting Cellular Cofactors in HIV Therapy

Viral Causes of Lymphoma: The History of Epstein-Barr Virus and Human T-Lymphotropic Virus 1

Discovery and Optimization of Novel Pyrazolopyrimidines as Potent and Orally Bioavailable Allosteric HIV-1 Integrase Inhibitors

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