Twice a year
A long-acting HIV drug of a new class has passed the first phase of clinical trials
Alice Bakhareva, N+1
Scientists from Gilead Sciences have developed and tested a new class of antiretroviral drug – a small molecule that disrupts the work of the HIV capsid protein and prevents the virus from multiplying at different stages. The researchers conducted the first phase of clinical trials with a single injection of the drug – it turned out to be safe, effective and remained in the blood for six months. The authors of the article published in the journal Nature (Link et al., Clinical targeting of HIV capsid protein with a long-acting small molecule) believe that the drug will be useful for patients who have developed multidrug resistance, as well as for prevention for people at risk.
Modern antiretroviral drugs save the lives of millions of people with the human immunodeficiency virus (HIV) and protect those at risk, but the virus is actively mutating and may acquire drug resistance. For people whose virus is resistant to several classes of antiretroviral drugs, it is difficult, and sometimes impossible, to choose a treatment. In addition, medications in the form of tablets must be taken daily, and omissions increase the likelihood of HIV reproduction and mutation. Therefore, it is necessary to look for drugs of new classes that will act for a long time and suppress the virus by a different mechanism.
Scientists from the American biopharmaceutical company Gilead Sciences, led by Stephen Yant, investigated the action of a small molecule GS-6207, an inhibitor of the viral capsid protein. First, its effect on the rate of capsid assembly and on HIV reproduction in cultures of various human immune cells was tested.
GS-6207 accelerated the assembly of capsid proteins, which caused the viral shells to deform. The drug proved to be more effective than all approved antiretroviral drugs: its semi-maximal effective concentration for HIV–infected cells was 105 picomoles per liter in the culture of T-helper cells, 32 and 56 picomoles per liter in the culture of primary T-cells and macrophages. GS–6207 was effective against two main forms of the virus - HIV-1 and HIV-2, including against types of virus resistant to modern drugs. In addition, the drug had virtually no cytotoxic effect on human cells.
HIV capsids: normal, when bound to GS-6207, immature (figures from the article Link et al.).
The structure of GS-6207, a protein-bound capsid, was studied using X-ray diffraction analysis. The molecule was well suited in shape to the site of the protein with which it was connected, interacted with it through electrostatic and hydrophobic bonds and connected two neighboring monomers – a loop was obtained that does not exist in the normal structure of the protein.
The structure of the capsid protein and the binding site of GS-6207.
An experiment with cells at different stages of infection showed that GS-6207 is effective both at the early and late stages of virus replication, although it is more effective at an early stage. Comparing the dynamics of the drug's action with reverse transcriptase and integrase inhibitors, the researchers suggested that GS-6207 acts after reverse transcription, but before the integration of viral DNA into the genome. Perhaps the drug does not allow viral DNA to penetrate into the nucleus, since this process is associated with the capsid protein.
The scientists also assessed how the virus develops resistance to the capsid protein inhibitor. To do this, cell cultures were infected with HIV-1 and GS-6207 was added to them, after a while it was isolated and injected into the culture of cells growing in an environment with a doubled concentration of the drug. The procedure was repeated ten times over three months, viral RNA was sequenced at each stage and the effectiveness of GS-6207 was determined.
After the fourth transplant on Wednesday, mutations began to appear in the capsid protein with a higher concentration of the drug, due to which viruses acquired resistance to GS-6207, but not other antiretroviral drugs. The mutated viruses had reduced the ability to replicate.
Finally, the researchers conducted the first phase of clinical trials of GS-6207, a randomized, placebo–controlled double-blind trial. At the first stage (a study of single increasing doses), 32 healthy volunteers were given different doses of the drug once (from 30 to 450 milligrams, a large dose was administered after they were convinced that the previous one did not cause adverse reactions), and eight were given a placebo. At the second stage, the same doses of GS-6207 were administered to 24 HIV-positive patients (eight more were administered placebo)
GS-6207 turned out to be safe and well tolerated – the most serious side effects were redness and pain at the injection site, which passed after a few days. The average half-life of the substance in the body was 38 days, it slowly and continuously penetrated into the blood from the injection site. At a dose of more than 100 milligrams, the concentration of the drug in the blood was effective (suppressed the reproduction of the virus by 95 percent) for 12 weeks, and at a dose of more than 300 milligrams – 24 weeks. Depending on the dose in HIV-infected patients, the logarithm of the number of viral particles in plasma decreased by 1.35-2.2 times in nine days.
The authors conclude that GS-6207 is the first effective and safe HIV capsid inhibitor, acts against both wild-type virus and drug-resistant strains and remains in the blood for a long time. After the end of clinical trials, it can be used both for patients who have taken many drugs and acquired multidrug resistance, and for the prevention of people at risk.
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