Anti-HIV-1 Integrase Drugs How Far from the Shelf

Abstract

Chemotherapy of HIV-1 infection/AIDS currently employs inhibitors of two products of the viral pol gene, the reverse transcriptase and protease enzymes. However, a third product of the pol gene is essential for retroviral multiplication, the integrase. As no cellular homologue of HIV integrase has been described, potential inhibitors could be relatively nontoxic. Development of HIV-1 integrase inhibitors could have favorable implication for combination therapy, including potential synergy with currently available inhibitors, as well as prevention of the chronic carrier state and the emergence of resistant mutants. Although several classes of putative integrase inhibitors that been described, still no clinically useful anti-integration drugs are available. It is the structural and functional complexity of the integration process together with the limitations of the available in vitro assays that has made it problematic to develop inhibitors of the HIV integrase. In this review we summarize current knowledge concerning the biology of this enzyme and of the integration process, and discuss major classes representatives of integrase inhibitors considering the obstacles to the development of true anti-integrase drugs.

Simultaneous determination of 1,5-dicaffeoylquinic acid and its active metabolites in human plasma by liquid chromatography–tandem mass spectrometry for pharmacokinetic studies

“…Development of HIV-1 integrase inhibitors could have favorable implication for combination therapy, including synergy with currently available inhibitors, as well as prevention of the chronic carrier state and the emergence of resistant mutants [19].…”

“…DNA integration is carried out by integrase, so HIV-1 integrase represents a key area in developing new antiretroviral therapy [14]. And as no cellular homologue of HIV-1 integrase has been described, this kind of potential inhibitors for HIV-1 integrase could be relatively nontoxic [11,[15][16][17][18][19]. DCQAs have been confirmed to be an effective HIV-1 integrase inhibitor [20] by selectively inhibiting HIV-1 integrase irreversibly toward its conserved amino acid residues in the central core domain of catalysis and preventing HIV-1 replication.…”

Accumulation and Intranuclear Distribution of Unintegrated Human Immunodeficiency Virus Type 1 DNA

“…Since efforts are currently being made to develop integrase inhibitors for AIDS therapy (18,48,52), a model system that allows the visualization of unintegrated HIV-1 DNA at the single-cell level might represent a useful tool to study the dynamics of the integration process. Here, we employed a novel method to distinguish in situ integrated from unintegrated HIV-1 DNA.…”

Preclinical Evaluation of GS-9160, a Novel Inhibitor of Human Immunodeficiency Virus Type 1 Integrase

“…The IN-DNA complex is then transported into the nucleus where IN performs concerted integration of both viral DNA ends into host chromosomal DNA by a reaction referred to as strand transfer. The integration of viral DNA into host chromosomal DNA is essential for HIV-1 replication, making the inhibition of HIV-1 IN function an attractive antiviral strategy (9,35,36,42).Historically, treatment of individuals infected with HIV-1 has relied on agents targeting two of the viral enzymes, reverse transcriptase and protease. Despite important clinical results achieved through the use of combinations of these agents, the continuous emergence of drug resistance remains a significant problem which fuels the need to discover novel drugs targeting other steps of the HIV-1 life cycle.…”

“…The IN-DNA complex is then transported into the nucleus where IN performs concerted integration of both viral DNA ends into host chromosomal DNA by a reaction referred to as strand transfer. The integration of viral DNA into host chromosomal DNA is essential for HIV-1 replication, making the inhibition of HIV-1 IN function an attractive antiviral strategy (9,35,36,42).…”