Integrase inhibitors
Integrase inhibitors represent a novel class of antiretroviral medications designed primarily to combat human immunodeficiency virus (HIV) infections, with potential applications for other retroviruses. These drugs function by inhibiting the integrase enzyme, which is crucial for the integration of viral DNA into the host cell's genome—a key step in the retroviral life cycle. Unlike older antiretroviral therapies that target reverse transcriptase and protease enzymes, integrase inhibitors offer a different mechanism of action, which can reduce the likelihood of viral resistance.
Raltegravir was the first integrase inhibitor approved by the U.S. Food and Drug Administration in 2007 and has demonstrated effectiveness in lowering viral load and increasing CD4-positive T cell counts in patients. Resistance to raltegravir can occur due to mutations in the integrase enzyme, prompting research into new derivatives to combat these resistant strains. Notably, integrase inhibitors are less likely to be toxic to human cells since there is no equivalent human enzyme, making them an important consideration in HIV treatment, especially for individuals with multidrug-resistant strains of the virus.
Integrase inhibitors
Definition
Integrase inhibitors are a new class of antiretroviral drugs developed to treat human immunodeficiency virus (HIV) infection and could theoretically be applied to other retroviruses. Integrase inhibitors block the action of an enzyme that catalyzes an important step in retroviral infection.
Retroviral Life Cycle
Retroviruses store their genetic material in the form of ribonucleic acid (RNA). Upon entering the target host cell, the reverse transcriptase enzyme uses the RNA genome as a template to synthesize a deoxyribonucleic acid (DNA) strand. In the cytoplasm, integrase binds to the viral DNA and begins processing the 3 end by removing nucleotides. Then, the integrase-DNA complex translocates to the cell nucleus, where the enzyme makes a staggered cut in the host DNA. Integrase joins the 3 end of the viral DNA to the 5 end of the host DNA by base pairing. The enzyme fills in the gaps of missing nucleotides and ligates the joined ends by forming covalent bonds.
Upon integration, the viral genome is copied and transcribed as part of the human chromosome. The enzyme protease cleaves peptides expressed from the viral genome into mature proteins that can be assembled into new virions, which are released from the host cell to complete the retroviral life cycle.
Antiretroviral Drugs
Older therapies block the activity of reverse transcriptase (with nucleoside and nucleotide reverse transcriptase inhibitors or with non-nucleoside reverse transcriptase inhibitors) or block maturation of viral proteins with protease inhibitors. Retroviruses can easily develop resistance to these drugs, because the reverse transcriptase and protease genes can undergo many base substitutions and still produce functional enzymes. These mutational changes alter protein conformation, making the enzymes harder to inhibit with a single drug.
When the integrase is inhibited, host enzymes circularize the provirus, which is then degraded, preventing stable integration into the host genome. There is no known human equivalent of the integrase enzyme, suggesting that this class of drugs is not likely to be toxic to the human cell.
Clinical Use
Raltegravir was the first integrase inhibitor to be approved by the US Food and Drug Administration (2007). It has been shown to reduce the amount of virus in the body (viral load) and to increase the number of CD4-positive T cells, which is one type of immune cell invaded by HIV.
Raltegravir is a derivative of diketobutanoic acid. HIV resistance to raltegravir is caused by mutations in locations near the active site; therefore, other diketobutanoic acids are being modified to tightly bind mutated integrases from resistant strains. Quinolone derivatives also appear to have anti-integrase effects.
Since the development and success of Raltegravir, several other integrase inhibitors have entered the market. Elvitegravir, also known as Vitekta, was approved by the FDA in 2012. It was followed by Dolutegravir and Biktarvy, both of which were approved in 2018. Cabotegravir followed in 2021. Several other drugs are also under development.
Impact
Resistance to antiretroviral agents has complicated efforts to treat HIV; therefore, the emergence of a new class of drugs that uses a different mechanism of action and carries a lower risk of resistance is welcome news for persons with multidrug-resistant strains.
Bibliography
Berger, Daniel S. “The Dawn of a New Treatment: A Look at Experimental HIV Integrase Inhibitors.” Positively Aware: The Monthly Journal of the Test Positive Aware Network 17 (2006): 44-45.
Fangman, John J. W., and Martin S. Hirsch. “Integrase Inhibitors and Other New Drugs in Development.” In AIDS Therapy, edited by Raphael Dolin, Henry Masur, and Michael S. Saag. 3d ed. New York: Churchill Livingstone/Elsevier, 2008.
Powell Key, Alyson. "Integrase Inhibitors for HIV: What to Know." WebMD, 11 Nov. 2024, www.webmd.com/hiv-aids/hiv-integrase-inhibitors. Accessed 3 Feb. 2025.
Rockstroh, Jürgen K. “Integrase Inhibitors: Why Do We Need a New Drug Class for HIV Therapy?” European Journal of Medical Research 14, suppl. 3 (2009): 1-3.