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Anti-AIDS drug saquinavir is a protease inhibitor

2020-05-15

Since its discovery in 1981, AIDS has become one of the greatest threats to human health in the 21st century. According to the incomplete statistics of the 2013 Global AIDS Report, there are 35 million patients in the world, and more than 5 million cases of HIV infection are added every year. If effective prevention and control cannot be achieved, it is expected that HIV infection will reach 200 million in 10 years.

 

Saquinavir, also known as diquinavir, saquinavir, saquinavir. The first protease inhibitor to market AIDS. Saquinavir, as the first HIV protease inhibitor approved by the FDA, has been used to treat patients infected with human immunodeficiency virus. Hypericin, the main component of Hypericum perforatum, has been proven to produce anti-RNA virus effects by inhibiting viral replication in vitro. Baicalin is a flavonoid compound extracted and isolated from the root of Scutellaria baicalensis, which can inhibit the replication of parainfluenza, influenza A, hepatitis B, HIV-1 and SARS coronavirus.

 

Saquinavir is a protease inhibitor and is mainly used clinically in combination with other antiretroviral drugs to treat human immunodeficiency virus (HIV) infection.

In HIV-infected cells, HIV protease specifically cleaves viral precursor proteins, enabling infectious viral particles to eventually form. These viral precursor proteins have decomposition sites and can only be recognized by proteases of HIV and its closely related viruses. Saquinavir is a peptoid that structurally mimics this type of decomposition site. Therefore, the active site of saquinavir and HIV-1 and 2 proteases can be tightly bound, showing reversible and selective inhibition of protease activity in vitro, but the affinity of human protease is about 50,000 times lower.

 

Unlike nucleoside analogues (Zidovudine, etc.), saquinavir acts directly on viral target enzymes without metabolic activation and has potential effects on resting cells. At a concentration of 10-10 mol / L, saquinavir has initial cultures of lymphoblasts and monocytes as well as lymphocytes and monocytes infected with laboratory virus strains or clinically isolated HIV-1 effect.

Laboratory cell culture results show that saquinavir is undergoing dual or triple therapy with other reverse transcriptase inhibitors (including AZT (zidovudine), DDC (zalcitabine), ddI (deoxyinosine)) During HIV-1 infection, there is an additional synergistic antiviral effect, but the toxicity does not increase.

 

In clinical studies, the changes in virus drug sensitivity (phenotypic resistance) and protease amino acid sequence (genotype resistance) in culture were studied. In patients who were treated with saquinavir and developed drug resistance, two protease mutant strains were isolated (L90M and G48V, the former is the main one, and the two are rare at the same time). A group of patients in Phase I / II clinical trials, combined with nucleoside analogues (DDC and/or AZT) treatment, had a genotype resistance rate of approximately 38% within a year (15 of 39 cases). The clinical significance of phenotypic and genotype changes associated with saquinavir therapy is not clear.

 

In phase III clinical trials NV14526 and SV14604, saquinavir combined with DDC (with/without AZT) for 1 year of treatment, the incidence of L90M was 20%, treatment for 24 weeks (2/81 cases) and 48 (2/75 Example) After a week, the incidence of G48V is about 2 ~ 3%. When saquinavir monotherapy, the occurrence of the above substitution phenomenon seems to be related to virus recurrence (12/13 cases). However, only a few recurring cases (6/22 cases) have substitution mutations.

 

Cross-resistance with other antiretroviral drugs: Saquinavir and reverse transcriptase inhibitors have few cross-resistances because the target enzymes of the two are different. HIV isolates resistant to AZT are still sensitive to saquinavir. Conversely, strains resistant to saquinavir are still sensitive to AZT. In a virus sensitivity study on protease inhibitors (saquinavir, indinavir, ritonavir, nelfinavir, amprenavir), 41 viruses were isolated from 37 patients. These patients were treated with saquinavir and / or nucleoside analogue RT inhibitors for 20 to 147 weeks, respectively. Among them, 22 strains are resistant to saquinavir. 27% (6/22 cases) of these patients had no cross-resistance to other inhibitors, and 8% (4/22 cases) showed extensive cross-resistance. Saquinavir treatment presents a unique and persistent virus mutation.


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