Inventory of the pathogenesis of AIDS and its related drugs

Source: Yaodu Written by: Serendipi.
WIT Editor: Amphetamine AIDS is a very dangerous disease, not only because it is an extremely fast and most widespread infectious disease, but also a very high mortality rate of disea.
However, the pathogenesis of HIV/AIDS, the development of therapeutic drugs and vaccines are still a worldwide problem and a research hotsp.
1 The pathogenesis of HIV/AIDS AIDS (acquired immunodeficiency syndrome, AIDS) is caused by human immunodeficiency virus (human immunodeficiency virus, HIV) infection, resulting in human defense function defects (especially cell-mediated immune function defects), and prone to A clinical syndrome of opportunistic infections and tumors develo.
The main route of infection is through sexual contact, blood and mother-to-child (pregnancy, childbirth, nursing) three ways of transmissi.
HIV is a single-stranded RNA virus, divided into HIV-1 and HIV-HIV-1 is the main type of HIV currently circulating in the world, accounting for about 95%, and HIV-2 is mainly confined to West Afri.
HIV mainly invades CD4+ T lymphocytes, resulting in a progressive decrease in the number of CD4+ T lymphocytes, impairing the body's cellular immune function until it is lost, and finally developing to AIDS, and even complicated by various serious opportunistic infections and tumo.
HIV is both lymphotropic and neurotrop.
In addition to mainly infecting CD4+ T lymphocytes, HIV can also infect mononuclear macrophages, B lymphocytes, natural killer (NK) cells, and microgl.
cells and bone marrow stem cel.
FigureThe life cycle of HIV (left); HIV cell invasion mechanism (right) The HIV viral code is expressed by reverse transcriptase, protease and integra.
Once HIV enters the target cell, the viral RNA is reverse transcribed into viral DNA under the action of reverse transcriptase, and integrated into the host cell chromosomal DNA by the action of endonuclease and integrase, and the integrated viral DNA transcribes viral gene RNA and messenger RNA, mature HIV particles are produced from synthetic viral proteins under the action of proteases, then released from the cell surface, and the virus repeats these steps to reprodu.
Therefore, blocking any step of the above-mentioned life cycle can effectively control the replication of HIV vir.
2 Anti-HIV/AIDS Drug Class 1 Reverse Transcriptase Inhibitors HIV is a retrovirus whose replication process relies on a unique enzyme, reverse transcriptase (RT), which reverse transcribes viral RNA into DNA provirus , so reverse transcriptase inhibitors can effectively inhibit the replication of the virus, is the earliest clinical application of anti-HIV/AIDS dru.
Reverse transcriptase inhibitors can be divided into nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTI.
cla.
NRTIs are analogs of deoxynucleotides, the DNA reverse transcriptase substrate for the synthesis of HIV, and are converted into active nucleoside triphosphate derivatives in vivo, which compete with natural deoxynucleoside triphosphates for binding to HIV .
Inhibits the role of RT and hinders the synthesis of provir.
The mechanism of action of NNRTIs is different from that of NRT.
They do not require phosphorylation activation, and directly bind to the P66 hydrophobic region of the RT catalytic active site of HIV, changing the conformation of the enzyme protein and inactivating it, thereby inhibiting the replication of HIV-NNRTIs do not inhibit cellular DNA polymerase, so they are less toxic, but at the same time are prone to drug resistan.
Clinically, NNRTIs are usually not used alone, but are used together with NRTIs, which can produce synergistic effec.
TableSome common reverse transcriptase inhibitors approved by the US FDA 2 HIV protease inhibitors In host cells, HIV has three genes expressed as polyproteins, namely gag, gag-pol and e.
HIV protease is an aspartyl protease encoded by the HIV gene and is required for viral replicati.
In the late stage of replication, proteases are responsible for specific cleavage at 8 different sites of the gag and gag-pol gene products to form mature structural and functional protei.
This processing makes the non-infectious virus infectio.
Therefore, HIV-1 protease plays a key role in the maturation and processing of the vir.
Inhibiting the activity of this enzyme produces immature progeny viruses that are incapable of infection, thereby preventing further infection by the vir.
Although HIV protease inhibitors (HIV Protese Inhibitors, PIs) can inhibit HIV replication, long-term application of protease inhibitors alone cannot completely eliminate the virus in the body, nor can it prevent the emergence of drug-resistant viruses in the bo.
Therefore, protease inhibitors are often used in combination with reverse transcriptase inhibito.
The bioavailability of protease inhibitors after oral administration is low, and the toxic and side effects caused by long-term use are obvious, and many HIVs have developed resistance to protease inhibito.
Therefore, new protease inhibitors need to be further develop.
TableSome common HIV protease inhibitors approved by the US FDA 3 Integrase inhibitors Integrase (Integrase) is an enzyme that helps retroviruses to integrate DNA carrying viral genetic information into the host's DNA, usually carried by the virus itself, and not present in host cel.
HIV-I integrase is an essential enzyme for retroviral replicati.

During HIV replication, it catalyzes the integration of viral DNA into host chromosomal DNA, which is a two-step process: the first step is called the 3' end process, which snips off two nucleotides from the 3' end of the viral DNA, exposing the The end is the hydroxyl group of CA (CAOH-3'); the second step is the insertion of a pair of viral DNA transcribed by reverse transcriptase into the host DNA, that is, the process of strand transf.

Viral DNA and host DNA then complete the entire integration process through binding repair, and integrase has no analogues in human cel.

Therefore, it becomes an attractive and reasonable target for the treatment of AI.

TableSome Common Integrase Inhibitors (Intergrase Inhibitors) 4 Fusion Inhibitors Approved by FDA Natural or synthetic polypeptides and small molecular compounds inhibit the pro-fusion function of gp41 by binding to the functional domain of gp4Targeting HIV-1 transmembrane glycoprotein gp41, it acts on the key link in the earliest stage of the virus life cycle, interfering with the adhesion or fusion of HIV and host cel.

FIs have shown good efficacy and safety in clinical treatme.

In recent years, with the deepening of the research on the molecular mechanism of the membrane fusion process and the function of gp41, new fusion inhibitor molecules targeting different functional regions of gp41 have been discovered, which has become one of the main research hotspots in recent yea.

One of the mainstream research directions to find breakthroughs in the field of AIDS treatme.

TableSome Common Fusion Inhibitors Approved by the US FDA 3 List of Representative Anti-HIV/AIDS Drugs List.

On August 12, 2013, the oral tablet with its sodium salt (Dolutegravir sodium) as the only active ingredient was approved by the US FDA for marketing under the trade name "TIVICA.

So far, dolutegravir sodium has been approved for marketing in more than 100 countries around the wor.

Dolutegravir sodium is one of GlaxoSmithKline's (GSK)'s best-selling HIV drugs, with global sales of around US$600 milli.

Dolutegravir is an integrase inhibitor that blocks the entry of HIV into cells and can be used in combination with other antiretroviral drugs as post-exposure prophylaxis and to prevent HIV infection after potential exposu.

On December 30, 2015, TIVICAY was approved by China's State Food and Drug Administration as a new drug for the treatment of adults and children over 12 years old with human immunodeficiency virus (HIV) infection in combination with other antiretroviral dru.

patien.

In addition, dolutegravir also has efficient antiviral activity and resistance to drug resistan.

At present, the synthetic route of dolutegravir has more than 6 steps to obtain the raw material dolutegrav.

Structural formula, source: Yaodu data Lamivudine (3TC) is a dideoxythiocytidine compound, which is an NRT.

There are β-D-(+)- and β-L-(-)- two isomers, both of which have strong anti-HIV-I effec.

However, its β-L-(1)-isomer has an antagonistic effect on the deamination of cytidine-deoxycytidine deamina.

The affinity of 3TC to reverse transcriptase is greater than that of human DNA polymerase, so it has a selective effe.

Lamivudine, as the first-generation nucleoside antiviral drug, has the earliest market ti.

It was approved by the US FDA in 199 The research and development company is GlaxoSmithKline (GSK), and it was introduced into the domestic market at the end of 199The synthetic route of Lamivudine is shown in the figure: FigureThe synthetic route of Lamivudine Yaodu data shows that in 2022, the drug dolutegravir/lamivudine/alfofur will be developed by Cipla Usa I.

Wei (Dolutegravir/Lamivudine/Tenofovir Alafenamide) was approved for marketi.

This is a combination of three drugs, which is more effective and can avoid drug resistance caused by a single dr.

It is also called highly active antiretroviral therapy (HAART) or cocktail thera.

The application of this therapy can inhibit the replication of the virus to the greatest extent, so that the damaged immune function can be partially or even fully recovered, thereby delaying the progression of the disease, prolonging the life of the patient and improving the quality of li.

3 Albuvirtide (ABT) Aikening (generic name: Albuvirtide) is a long-acting HIV fusion inhibitor independently developed by China's pharmaceutical company Frontier Biopharmaceutical (Nanjing) .

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Its 2018 In the clinical treatment after it was approved and marketed in China in 2009, it showed the characteristics of broad spectrum, long-acting, fast onset, high safety, strong efficacy and small drug interactio.

Aibovirtide is a long-acting fusion inhibitor targeting HIV virus membrane protein gp41, consisting of 34 amino acids and a modified chemical gro.

Aibovirtide acts on the first link of HIV-1 virus infection, binds to the target HIV-1 membrane protein gp41, inhibits the fusion of the viral membrane with the human CD4 cell membrane, thereby preventing HIV-1 virus from entering cells and exerting its antiviral effe.

Through the specific binding of its side chain modification group to albumin in blood at a molecular ratio of 1:1, Aibovirtide forms a stable conjugate, which prolongs its half-life in vivo and achieves a long-term functi.

Aibovirtide is a polypeptide drug with a molecular weight of 4666, which is 10 times that of other oral dru.

Polypeptides will be metabolized into amino acids in the human body, will not attack human cells, and are highly sa.

At the 11th International AIDS Association AIDS Science Conference (IAS) in 2021, Frontier Bio announced the main research results of the phase III clinical trial (TALENT study) of Aibovirtide: The TALENT study is the world's first use of long-acting injectable dru.

The Phase III clinical trial of the two-drug formula for the treatment of HIV-infected patients who failed initial treatment is the first Phase III clinical trial of an original new AIDS drug in China, and the first registered clinical trial of a new AIDS drug with Asian population as the research obje.

The results of this study show that the two-drug regimen with ebavitaxel as the core to replace two NRTIs in the treatment of HIV-1 infected patients who failed initial treatment can achieve rapid and durable viral suppression, and the treatment is non-inferior to the standard second-line and third-line drugs for 48 wee.

combination thera.

Abovavirtide has the advantages of high drug resistance barrier, no injection site reaction, high patient compliance with long-term weekly injection and good overall safe.

Taking Aibovirtide as the core and combining it with other antiretroviral drugs, it is a new and simplified two-drug therapy for the treated patien.

A major breakthrough in AIDS dru.

FigureMechanism of action of Aibovirtide4 AzvudineFigureChemical structural formula of Azvudine, source: Yaodu data Azvudine was developed by Zhengzhou University and Henan Provincial Analysis and Testing Research Center The new AIDS drug was successfully developed by the team led by Professor Chang Junbiao from Henan Normal Universi.

On April 30, 2013, it was approved to enter clinical trials by the State Food and Drug Administration; in May 2013, it was authorized by China's invention patent and submitted an international application through the Patent Cooperation Treaty (PCT); on July 21, 2021, the national The National Medical Products Administration announced that it has passed the priority review and approval process and conditionally approved the marketing of the Class I innovative drug Azvudine Tablets submitted by Henan Zhenzhen Biotechnology .

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This medicine is used in combination with nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors to treat adult HIV-1 infected patients with high viral lo.

Azvudine is a novel inhibitor of nucleoside reverse transcriptase and accessory protein Vif, and the first dual-target anti-HIV-1 drug mentioned above, which can selectively enter CD4 cells in peripheral blood mononuclear cells of HIV-1 target cells Or CD14 cells, play a role in inhibiting virus replicati.

Such characteristics make its clinical research results show that as long as a very small dose of oral drugs (only 1% of the dosage of another anti-AIDS drug lamivudine) can achieve an effective concentration of inhibiting the virus, so its medication The dose is sma.

Another feature is its long-lasting effe.

Studies have shown that it can still inhibit the replication of human immunodeficiency virus by 100% within 4 days after a single dose, which shows that it can also be used to prevent HIV-exposed people from contracting AI.

In addition, it has the advantages of low drug resistance and high effica.

The synthetic route of Azvudine is shown in the figure: FigureSynthetic route of AzvudineAnticancer and antiviral mechanism of action of Azvudine 4 Conclusions 3-day UN General Assembly AIDS on June 8, 2021 A high-level meeting on the issue convened and adopted a new global political declaration on AIDS, drafted by UNAI.

The adoption of the political declaration will mean that all member states of the United Nations commit to and act on the fight against AIDS in order to achieve the goal of ending AIDS by 203In the absence of effective vaccines and HIV eradication treatments and drugs, there is still a significant clinical need for AIDS prevention and treatme.

The research and development of preventive vaccines, new compound single-piece preparations, long-acting injectable drugs, drugs with new mechanisms of action, and broad-spectrum neutralizing antibody-mediated immunotherapy, drug-free remission and functional cure will be the hot spots for future anti-AIDS drug research and developme.

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Of course, the task of ending AIDS is arduous and requires practical actions and efforts, and we have a long way to .

An Economical Route to Lamivudine Featuring a Novel Strategy for Stereospecific Assembly[.

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