How do integrase inhibitors help stop HIV?
Integrase inhibitors rely on the fact that HIV needs integrase to replicate. These drugs stop HIV from being able to make integrase. Without the help of this enzyme, HIV can’t take over the T cells to copy itself. With a combination of other HIV medications, integrase inhibitors can help keep HIV under control.
How do integrase strand transfer inhibitors work?
The integrase strand-transfer inhibitors bind metallic ions at the insertion site in the T-cell DNA, preventing the viral DNA strand transfer by the integrase enzyme. The viral DNA is then degraded and cannot multiply.
How does raltegravir inhibit HIV replication?
Raltegravir inhibits integration at an IC50 of ~10 nM and the results are consistent with inhibition of the third step of the integration process (i.e. strand transfer). This prevents the incorporation of linear HIV-1 cDNA into the host cell’s genome and disrupts the viral life cycle of HIV.
How does HIV use integrase?
An enzyme found in HIV (and other retroviruses). HIV uses integrase to insert (integrate) its viral DNA into the DNA of the host CD4 cell. Integration is a crucial step in the HIV life cycle and is blocked by a class of antiretroviral (ARV) HIV drugs called integrase strand transfer inhibitors (INSTIs).
How does insti drug work?
Integrase inhibitors (INSTIs) are a class of antiretroviral drug that prevents HIV from inserting its genetic code into the DNA of an infected cell. It does this by blocking an enzyme known as integrase that HIV needs to hijack the host cell’s DNA and start churning out copies of itself.
What is the function of integrase?
Integrase is the viral enzyme that catalyzes the integration of virally derived DNA into the host cell DNA in the nucleus, forming a provirus that can be activated to produce viral proteins.
How does integrase work?
Integrase catalyzes nucleophilic attack of the 3′ hydroxyl group at the ends of the processed DNA on a pair of phosphodiester bonds in the target DNA (DNA strand transfer). Cellular enzymes complete integration by repairing the resulting integration intermediate.
Is Raltegravir a competitive inhibitor?
Raltegravir and elvitegravir share the same mechanism of action against integrase: to bind to the active site of Mg2+ ions. Competitive inhibitors compete directly with viral DNA for binding to integrase in order to inhibit 3′-end processing.
What does raltegravir interact with?
It is likely that the same dose recommendation will be applicable when raltegravir needs to be combined with other strong UGT inducers such as phenytoin and phenobarbital. Raltegravir is better absorbed in an environment with a higher pH and hence a drug-drug interaction study with an acid reducing agent was indicated.
What does the viral enzyme integrase do?
What is integrase activity?
Integrase possesses two major catalytic activities: an endonucleolytic cleavage at each 3′-OH extremities of the viral genome, named 3′-processing, and a strand transfer reaction leading to the insertion of the processed viral DNA into the target DNA by a trans-esterification mechanism.
Which is an integrase inhibitor?
Integrase inhibitors (INIs) are a class of antiretroviral drug designed to block the action of integrase, a viral enzyme that inserts the viral genome into the DNA of the host cell. Since integration is a vital step in retroviral replication, blocking it can halt further spread of the virus.
How do integrase strand-transfer inhibitors work?
The integrase strand-transfer inhibitors bind metallic ions at the insertion site in the T-cell DNA, preventing the viral DNA strand transfer by the integrase enzyme. The viral DNA is then degraded and cannot multiply. The INSTIs have a high barrier to resistance development by HIV, especially the second generation INSTIs.
What are the major integrase inhibitor (INSTI) resistance mutations?
Major Integrase Inhibitor (INSTI) Resistance Mutations Consensus 66 T 143 Y 147 S Bictegravir (BIC) K Dolutegravir (DTG) K Elvitegravir (EVG) AIK G Raltegravir (RAL) AIK RCH
What are INSTIs for HIV?
INSTIs are often a part of fixed-dose, single pill, combination drug formulations for ART. INSTIs, as a part of a complete ART regimen, are approved for treatment of children with HIV infection, who are 12 or older and weigh at least 40 kg. INSTIs are effective as initial therapy in controlling viral growth in treatment-naive HIV patients.
What is the relationship between INSTI susceptibility and virological response?
Mutations in bold reduce INSTI susceptibility or virological response. Mutations in plain text contribute to reduced suceptibility in combination with other INSTI-resistance mutations.