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Human immunodeficiency virus (HIV) continues to be a major contributor to morbidity and mortality worldwide, particularly in developing nations where high cost and logistical issues severely limit the use of current HIV therapeutics. This, combined HIV's high propensity to develop resistance, means that new anti-viral agents against novel targets are still urgently required. We previously identified novel anti-HIV agents directed against the nuclear import of the HIV Integrase (IN) protein, which plays critical roles in the HIV lifecycle inside the cell nucleus, as well as in transporting the HIV pre-integration complex (PIC) into the nucleus. Here we investigate the structure activity relationship of a series of these compounds for the first time, including a newly identified anti-IN compound, Budesonide, showing that the extent of binding to the IN core domain correlates directly with the ability of the compound to inhibit IN nuclear transport in a permeabilised cell system. Importantly, compounds that inhibited the nuclear transport of IN were found to significantly decrease HIV viral replication, even in a dividing cell system. Significantly, Budesonide or its analogue Flunisolide, were able to effect a significant reduction in the presence of specific nuclear forms of the HIV DNA (2-LTR circles), suggesting that the inhibitors work though blocking IN, and potentially PIC, nuclear import. The work presented here represents a platform for further development of these specific inhibitors of HIV replication with therapeutic and prophylactic potential.
This article was published in the following journal.
Name: Cellular microbiology
Bictegravir (BIC) and cabotegravir (CAB) are the latest available HIV integrase inhibitors in clinical trials. The combination of major integrase inhibitor substitutions G140S/Q148H has been shown to ...
Impact of transmitted HIV-1 drug resistance on the efficacy of first-line antiretroviral therapy with two nucleos(t)ide reverse transcriptase inhibitors plus an integrase inhibitor or a protease inhibitor.
To examine the impact of transmitted drug resistance (TDR) on response to first-line regimens with integrase strand transfer inhibitors (INSTIs) or boosted protease inhibitors (bPIs).
Serine integrases catalyze the site-specific insertion of viral DNA into a host's genome. The minimal requirements and irreversible nature of this integration reaction has led to the use of serine int...
Integrase strand transfer inhibitors (INSTIs) are recommended by international guidelines as first-line therapy in antiretroviral-naive and -experienced HIV-1-infected patients.
Nuclear pore complexes (NPCs) orchestrate cargo between the cytoplasm and nucleus and regulate chromatin organization. NPC proteins, or nucleoporins (Nups), are required for human immunodeficiency vir...
This 2 arm study will evaluate the efficacy and safety of Fuzeon with an integrase inhibitor in an expanded access program plus optimized background in HIV-1 infected patients naive to Fuz...
Integrase is an enzyme produced by HIV so that the virus can multiply in the human body. GSK1349572 is a new drug in the integrase inhibitor class that prevents the enzyme from working pro...
The presence of a pool of cells latently infected by HIV-1 in patients taking HAART and with a viral load below 50 copies/mL is the main limitation to eradication of the virus from the bod...
GSK1349572 is an integrase inhibitor that will be evaluated for the treatment of HIV infection. This phase IIa, multicenter, randomized, parallel, double-blind, dose ranging, placebo-contr...
The purpose of this study is to measure the decay characteristics of HIV in the blood of patients after taking a combination of anti-HIV drugs, which includes a new class of anti-HIV drug,...
Inhibitors of HIV INTEGRASE, an enzyme required for integration of viral DNA into cellular DNA.
The integration of exogenous DNA into the genome of an organism at sites where its expression can be suitably controlled. This integration occurs as a result of homologous recombination.
Dissection in the neck to remove all disease tissues including cervical LYMPH NODES and to leave an adequate margin of normal tissue. This type of surgery is usually used in tumors or cervical metastases in the head and neck. The prototype of neck dissection is the radical neck dissection described by Crile in 1906.
A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.
Compounds which inhibit or antagonize biosynthesis or actions of integrase.
Human Immuno Deficiency Virus (HIV)
Human Immunodeficiency Virus (HIV), the causative agent of AIDS. The Human Immunodeficiency Virus, more commonly known as HIV, is a member of the lentivirus sub-set of the retrovirus family of pathogens. It causes AIDS, or Acquired Immuno Deficiency Sy...
AIDS and HIV
AIDS; Acquired Immune Deficiency Syndrome. HIV; Human Immunodeficiency Virus HIV infection causes AIDS. HIV infection also causes the production of anti-HIV antibodies, which forms the test for HIV in patients. People who have the HIV antibodies are ...