A historical sketch of the discovery and development of HIV-1 integrase inhibitors

  title={A historical sketch of the discovery and development of HIV-1 integrase inhibitors},
  author={Andrea Savarino},
  journal={Expert Opinion on Investigational Drugs},
  pages={1507 - 1522}
  • A. Savarino
  • Published 15 November 2006
  • Biology
  • Expert Opinion on Investigational Drugs
The long process of HIV-1 integrase inhibitor discovery and development can be attributed to both the complexity of HIV-1 integration and poor ‘integration’ of these researches into mainstream investigations on antiretroviral therapy in the mid-1990s. Of note, some fungal extracts investigated during this period contain the β-hydroxyketo group, later recognised to be a key structural requirement for keto-enol acids (also referred to as diketo acids) and other integrase inhibitors. This review… 

Authentic HIV-1 integrase inhibitors.

A number of patented HIV-1 IN inhibitors, especially those that possess high selectivity for the strand transfer reaction, are reviewed, particularly those that have a polar coplanar moiety.

HIV-1 IN inhibitors: 2010 update and perspectives.

An update on the IN inhibitors reported in the last two years, including second generation STI, recently developed hydroxylated aromatics, natural products, peptide, antibody and oligonucleotide inhibitors, and the targeting of IN cofactors such as LEDGF and Vpr will be discussed as novel strategies for the treatment of AIDS.

HIV-1 Integrase Inhibitors

The results from advanced stages of human clinical trials with HIV-1 integrase (IN) inhibitors indicate a promising future for these compounds as a novel class of antiretroviral drugs.

Anti-infectives Clinical progress of HIV-1 integrase inhibitors

The development of strand transfer-specific inhibitor classes is an important achievement for the IN drug design and development field, but continued drug development is needed given that the ability of HIV to replicate under therapeutic pressure will undoubtedly lead to the emergence of IN drug-resistant viral strains.

Development and Identification of a Novel Anti-HIV-1 Peptide Derived by Modification of the N-Terminal Domain of HIV-1 Integrase

Results confirmed peptide 25 as a hit for further development of new chemotherapeutic agents against HIV-1 and identified two nonapeptides, that show a potency of inhibition similar to the one of peptide 18.

HIV‐1 integrase inhibitors: 2005–2006 update

A comprehensive report of all IN inhibitors discovered in the years 2005 and 2006 is provided to provide a continued effort toward the discovery of novel inhibitors to keep a therapeutic advantage over the virus.

Identification of a dibenzocyclooctadiene lignan as a HIV-1 non-nucleoside reverse transcriptase inhibitor

A dibenzocyclooctadiene lignan, termed HDS2 was identified that possessed anti-HIV activity against a wide variety of viral strains with EC50 values in the 1–3 µM range and provides a new scaffold for further optimization of activity through structure-guided design.

New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action

It is shown that in addition to the properties already known for LEDGINs, the binding of tBPQAs to the IN dimer interface inhibits IN enzymatic activity in a LEDGF-independent manner, and this inhibition occurs at or prior to the viral DNA 3′-processing step.

Naphthoxazepine Inhibitors of HIV‐1 Integrase: Synthesis and Biological Evaluation

Two sets of compounds derived from the fusion of a diversely annulated naphthoxazepinedione system with 1,3‐thiazole and 1, 3‐oxazole are described, gaining further insight into the structure–activity relationship of this class of IN inhibitors.



Patented small molecule inhibitors of HIV-1 integrase: a 10-year saga

The first review of the entire patent literature for small molecule intergrase inhibitors is presented, based on compounds with potential to serve as leads, therefore, no attempts are made to include: antibodies, oligonucleotides or polypeptides.

Design and development of integrase inhibitors as anti-HIV agents.

A review is presented on different categories of compounds that have been studied for the inhibition of the HIV-1 integrase to develop anti-HIV agents and the important structural features essential for the inhibitor of the integrase are pointed out.

Integrase inhibitors to treat HIV/Aids

This review focuses on the molecular basis and rationale for developing integrase inhibitors, as well as the main classes of lead compounds and interfacial inhibitors of protein–nucleic-acid interactions that might apply to the clinically used strand-transfer inhibitors.

Novel HIV-1 integrase inhibitors derived from quinolone antibiotics.

The modification of a quinolone antibiotic is described to produce the novel integrase inhibitor JTK-303 (GS 9137) that blocks strand transfer by the viral enzyme.

Structure-activity relationships of HIV-1 integrase inhibitors--enzyme-ligand interactions.

HIV-1 integrase is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA and appears to have no functional equivalent in human cells.

Patented HIV-1 integrase inhibitors (1998-2005).

  • P. Cotelle
  • Biology, Medicine
    Recent patents on anti-infective drug discovery
  • 2006
The present article reviews the increasing number of patents on small molecule HIV-1 integrase inhibitors in the 1998-2005 period, from the pioneer ones (discovery of selective strand transfer inhibitors) to the last patents including the actual molecules under clinical trials.

Discovery of natural product inhibitors of HIV-1 integrase at Merck

The evaluation of over 200,000 extracts originating from more than 50,000 microbial strains equally represented by fungi and actinomycetes led to the discovery of 24 novel classes of chemically diverse natural product inhibitors of HIV-1 integrase, representing a wide variety of classes with molecular weights ranging from 180-1,663 Da and HIV- 1 integrase-inhibitory activity IC 5 0 values ranging from 50 nM to > 100 μM.

HIV‐1 integrase inhibitors: 2005–2006 update

A comprehensive report of all IN inhibitors discovered in the years 2005 and 2006 is provided to provide a continued effort toward the discovery of novel inhibitors to keep a therapeutic advantage over the virus.

Inhibition of HIV-1 integrase activity by synthetic peptides derived from the HIV-1 HXB2 Pol region of the viral genome.

Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: a platform for antiviral drug design.

  • Y. GoldgurR. Craigie D. Davies
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
The structure of a complex of the HIV-1 integrase core domain with a novel inhibitor, 5ClTEP, 1-(5-chloroindol-3-yl)-3-hydroxy-3-(2H-tetrazol-5-yl)pro penone, to 2.1-A resolution is determined.