What Are Antivirals?

Antiviral drugs are a class of drugs used to prevent and treat viral infections. It can inhibit virus replication enzymes in vitro, inhibit virus replication or reproduction in infected cells or animals, and is an effective drug for treating viral diseases in clinical.

Viruses are the smallest of pathogenic microorganisms. The core contains nucleic acid (ribonucleic acid RNA or deoxyribonucleic acid DNA) and replicase. It has a protein shell and membrane. It has no cell structure and lacks a complete enzyme system. It must rely on the host. Cells and enzymes for reproduction (replication)

Introduction to antiviral drugs

Antivirals Antiviral drugs are a class of drugs used to prevent and treat viral infections. It can inhibit virus replication enzymes in vitro, inhibit virus replication or reproduction in infected cells or animals, and is an effective drug for treating viral diseases in clinical. Viruses are the smallest of pathogenic microorganisms. The core contains nucleic acid (ribonucleic acid RNA or deoxyribonucleic acid DNA) and replicase. It has a protein shell and membrane. It has no cell structure and lacks a complete enzyme system. The cells and enzymes multiply (replicate), and its replication process is divided into four stages:

Adsorption. The virus is adsorbed on susceptible cell protein receptors.

Invasion. The virus enters the cell.

Nucleic acid replication. After the virus enters the cell, it unshells, the viral nucleic acid is released, and the nucleic acid is replicated.

Viral acid and structural protein are assembled into a complete virus after synthesis.

Antiviral drugs mostly inhibit the enzymes required for their reproduction at different stages of their replication and reproduction, thereby blocking their replication. The mechanisms of virology and molecular biology on virus-specific enzymes, virus replication, and antiviral drugs have been elucidated. People continue to find some antiviral drugs that selectively and specifically act on viruses. Important viral diseases, such as influenza, herpes infection, acquired immunodeficiency syndrome, hemorrhagic fever, hepatitis B, etc.

Antiviral drugs

Antiviral interferon

[Drug name] Interferons [Mechanism of action] This product is a class of antiviral glycoprotein substances produced by vertebrate cells after viral infection and other stimuli. For viral infections, such as viral keratitis, hepatitis, influenza, etc., as well as the treatment or adjuvant treatment of malignant tumors.

[Caution] No obvious adverse reactions have been seen.

Antiviral iodoside

Iodoside (IDH) inhibits DNA viruses (viruses with a nucleic acid component of DNA) such as herpes simplex virus type I, vaccinia virus, and adenovirus. The mechanism of action is that iodoside and thymidine compete for phosphorylase and polymerase, inhibit virus synthesis of DNA or form non-infectious DNA, and stop virus reproduction. Because of its systemic toxicity, it is teratogenic and mutagenic, so only 0.1% eye drops and 0.5% eye ointment can be used to treat herpes simplex keratitis.

Trifluorothymidine

Trifluorothymidine (TFT) is an iodoside analog with antiviral effects similar to iodoside and slightly better water solubility.

Adenosine arabinoside

Ara-A (Ara-A) adenine nucleoside analog, is the first injection. Drugs for the treatment of herpes simplex virus encephalitis. Mechanism of action: Thymidine kinase acts in the cell to phosphorylate monophosphates, diphosphates, and triphosphates, and its adenosine triphosphate is an active substance that competitively binds to viral DNA polymerase to inhibit Its activity also inhibits nucleotide reductase and deoxynucleotidyl transferase, thereby inhibiting viral DNA synthesis. This product is a broad-spectrum anti-DNA virus drug, which can inhibit herpes virus type , type , herpes zoster virus, cytomegalovirus and EB virus. Topical eye ointment can treat herpetic keratitis, and intravenous drip for lethality Herpes encephalitis, due to poor water solubility, requires intravenous drip at the same time as glucose injection. It can also be used for shingles in immunodeficiency patients. Its derivative, adenosine-5'monophosphate, is 400 times more water-soluble than the former. Available for intramuscular and intravenous injection. Adverse reactions: vomiting, nausea, loss of appetite, diarrhea, and mild bone marrow suppression may occur in large doses, and recover after stopping treatment. Patients with renal insufficiency, nephrectomy, or kidney transplantation, Ara-A is excreted slowly, and it is easy to accumulate poisoning. Use with caution.

Ribavirin

Ribavirin (RBV) can quickly enter cells, which is phosphorylated into triphosphates by cellular adenosine kinase in cells, inhibits viral RNA transcriptase, blocks viral DNA synthesis, and inhibits inosine monophosphate dehydrogenase , Inhibit guanosine synthesis, thereby inhibiting the synthesis of viral RNA and DNA. Clinical application of 0.5% eye drops for viral keratitis. Nasal or aerosol inhalation of 1% solution for upper respiratory tract infection. Intravenous treatment of adenovirus pneumonia and hemorrhagic fever in children. Oral for the treatment of hepatitis A, can reduce aminotransferase and serum bilirubin. Adverse reactions: long-term application of large doses can cause anemia, increased free bilirubin, increased reticulocytes, and can be recovered after drug withdrawal. Changes in liver function have been reported orally.

Acyclovir

Acyclovir (ACV) is a nucleoside analog. The anti-herpes simplex virus type and and herpes zoster virus EB virus are not effective against cytomegalovirus and are also effective against hepatitis B virus. Acyclovir in cells infected with herpes simplex virus, combined with virus-specific thymidine kinase, phosphorylates ACV into monophosphate compounds, and then phosphorylates into diphosphates and triphosphates, and triphosphates The compound is an active substance against herpes virus and inhibits the synthesis of herpes virus DNA polymerase and viral DNA. This medicine is a specific medicine for treating herpes simplex type and virus and herpes zoster virus infection. It also has a certain effect on Epstein-Barr virus infection infectious mononucleosis and hepatitis B. For the treatment of herpes keratitis, genital herpes, systemic shingles and herpes encephalitis. Severe systemic herpes can be treated by intravenous infusion, once every 8 hours for 7 to 10 consecutive days, or orally, 5 times a day, and quickly controlled development and cured in 7 days. Has been tried for the treatment of viral hepatitis B, long-term application, with certain effects. This product is used in combination with AZF to reduce dosage and toxic side effects. Symptoms can be significantly improved in patients with advanced acquired immunodeficiency syndrome complicated by herpes virus infection. The drug is not highly water soluble, and a large number of intravenous drips can cause renal tubular obstruction. Intravenous occasionally saw elevated levels of urea nitrogen and creatinine, dry mouth, and can be recovered after drug withdrawal or reduction. Renal dysfunction and infants with low excretory function need to reduce the dose.

Propoxyuridine

Propoxyuridine (DHPG) is an acyclic guanosine analogue. Its antiviral effect is similar to that of acyclic guanosine, its activity is better than that of acyclic guanosine, and it can inhibit cytomegalovirus. . Used to treat severe cytomegalovirus infections, AIDS and cytomegalovirus retinitis.

Azidothymidine

Azidothymidine (AZT) is a nucleoside drug. First anti-human immunodeficiency virus (HIV) drug. This product can be phosphorylated into triphosphate (AZTTP) in cells infected with HIV to competitively inhibit viral reverse transcriptase. Deoxythymidine triphosphate replaces the virus's cDNA, which causes the DNA chain to grow for life, thus hindering the virus. Reproduction. AZTTP has a 100-fold stronger affinity for HIV virus reverse transcriptase than cell polymerase, and therefore has stronger inhibition of HIV and less cytotoxicity. Its antiviral effect is highly selective. It can be used to treat acquired immunodeficiency syndrome and AIDS-related relapse (patients with HIV infection with T4 lymphocytes below 300 / mm2, weight loss, lymphadenopathy, and fever). This medicine is taken orally 4 to 6 times a day for 16 to 21 weeks continuously; intravenously, once every 4 hours, and changed to oral administration after 2 weeks. Adverse reactions include bone marrow suppression, anemia, leukocytopenia, headache, weakness, fever, chills, chest and back pain, poor stomach appetite, occasional rash, and the adverse reactions disappeared after discontinuation. As the acquired immunodeficiency syndrome is associated with multiple infections and conditions, such as pneumocystis pneumonia, toxoplasmosis, sporozoosis, fungal bacterial infections, and cytomegalovirus, herpes virus, or enterovirus infections, several drugs must be used simultaneously. Pay close attention to adverse drug reactions.

Dideoxyinosine

Dideoxyinosine (DDI) is an azide deoxythymidine analog, and its anti-human immunodeficiency virus effect is similar to that of azide deoxythymidine. It is effective against azide deoxythymidine-resistant human immunodeficiency virus and has low toxicity.

Amantadine

Inhibition of influenza virus type A, not effective against type B. The mechanism of action is to change the surface charge of the host cell membrane, affect the fusion of the virus and the infected cells, and block virus husking and nucleic acid release in the cell. It is used to prevent and treat upper respiratory tract infection caused by influenza A virus. Can cause neurological side effects such as headache.

Rimantadine

The effect is similar to that of amantadine. These two drugs are taken orally during the influenza A epidemic period, twice a day for a total of 6 weeks, and have a protection rate of 85 to 90%. The adverse reactions to the central nervous system are lower than that of amantadine.

Morphoguanidine

It has inhibitory effect on a variety of viruses (influenza virus, parainfluenza virus, rhinovirus, coronavirus, and adenovirus), but the curative effect is not exact and it is now rarely used. Adverse reactions: Can interfere with color vision and have reactions such as loss of appetite.

Phthalamide

Topical anti-herpes virus created in China. This product was originally a Chlamydia trachomatis drug. In vitro tests inhibited herpes virus types and at a concentration of 2 g / ml of phthalamide dimethyl sulfoxide solution. The mechanism of action is mainly inhibition of viral DNA and early protein synthesis. Clinically, 0.1% phthalamidine dimethyl sulfoxide solution and ointment are used to treat skin herpes and shingles.

Foscarnet

Phosphonic acid (PFA) pyrophosphate polymer has a broad-spectrum antiviral effect and inhibits herpes simplex type I and II viruses, hepatitis B virus, cytomegalovirus, and influenza virus. The mechanism of action is mainly to inhibit virus-specific DNA polymerase and reverse transcriptase, thereby inhibiting virus proliferation. In ducks, it has a certain inhibitory effect on duck hepatitis B virus polymerase and DNA. Intravenous drip for cytomegalovirus infection. It has been reported that this product treats 8 cases of fulminant hepatitis with mixed infection of hepatitis B and hepatitis D, and 6 cases survive and recover completely. In patients with chronic persistent hepatitis and chronic active hepatitis, HBV-DNA levels decreased after treatment, but increased after stopping the drug. Only one case of e antigen turned negative and e antibodies appeared. When the dose is too large, there are adverse reactions such as nausea and vomiting, and the reduction will recover.

Isoprinosine

The mechanism of action is to improve the host's immune function to exert antiviral effects. Can inhibit the replication of many DNA and RNA viruses in cell culture. After double-blind tests, oral administration of this product can reduce the onset time and severity of various viral infections, and is conducive to recovery for patients with acquired immunodeficiency syndrome and tumors. This product is used to treat 59 cases of acute viral hepatitis B, 4 a day For 28 days, it was significantly better than the control group in terms of fatigue, improved appetite, and liver swelling. Total bilirubin, transaminase value, and HbsAg titer decreased, and no adverse reactions were seen. This medicine has not been recognized internationally.

Antiviral effects also include interferon, interleukin and other biological agents, as well as a variety of plant drugs, Chinese herbal medicine.

Classification of antiviral drugs

Antiviral nucleosides

Nucleosides are composed of bases and sugars. Various ribonucleosides or deoxyribonucleosides formed by one of five natural bases (A, C, T, U, G) and ribose or deoxyribose are called natural nucleosides. Nucleosides formed after bases or groups in glycosyl groups are called synthetic nucleosides, and these synthetic nucleosides may become inhibitors of natural nucleosides, inhibiting the DNA or RNA polymerase activity of viruses or host cells , Stop the synthesis of DNA or RNA and kill the virus.

Nucleoside analogs can be divided into non-open-loop and open-loop based on their structure.

1. Non-open-loop nucleosides

Nucleoside antiviral drugs usually need to be converted into triphosphates in the body to function, which is the common mechanism of action of such drugs.

Zidovudine is an analog of thymidine, which is substituted with an azide group at the 3-position of its deoxyribose moiety. It can inhibit the RNA tumor virus of HIV and T-cell leukemia that can cause AIDS. Antiretroviral drugs.

Zidovudine enters HIV-infected cells. It is first acidified by thymidine kinase, thymidine kinase, and nucleoside diphosphate kinase phosphorylation in host cells to generate 5-triphosphate zidovudine and play a role.

Zidovudine is sensitive to light and heat, so zidovudine should be kept away from light at 15 ~ 25 .

Zidovudine has good absorption in the gastrointestinal tract, oral bioavailability is 60% to 70%, half-life is about 1 hour, and is higher in body tissues and cerebrospinal fluid. After zidovudine is introduced into the human body, it is quickly metabolized by glucuronic acid to produce a 5-oxyglucuronide metabolite after the first pass metabolism by the liver. The plasma elimination half-life of this metabolite is similar to zidovudine, but No anti-HIV effect. Another metabolite is 3-amino-3-deoxythymidine, which has a low plasma concentration and may be related to myelosuppressive toxicity.

Zidovudine's main toxicity is myelosuppression, which manifests as anemia. Therefore, 30% to 40% of patients after treatment have severe anemia and granulocytopenia, and regular blood transfusions are required.

Stavudine is a dehydrated product of deoxythymidine. It introduces 2 , 3-double bonds and is an unsaturated thymidine derivative. Stavudine is stable to acids, has good oral absorption, and has a short plasma half-life of 1-2 hours. A large amount of the drug is excreted from the urine as a prototype.

Stavudine's mechanism of action is similar to zidovudine. When it enters human cells, it gradually phosphorylates at the 5 position to generate triphosphates, thereby inhibiting reverse transcriptase activity and breaking DNA bonds. Stavudine has the same inhibitory effect on HIV-1 and HIV-2, and the HIV-virus strain that produces resistance to zidovudine has an inhibitory effect, but the bone marrow toxicity is more than 1/10 of zidovudine. Stavudine is suitable for AIDS and related syndromes that cannot tolerate or treat ineffectiveness such as Zidovudine and Zacitabine.

Lamivudine is a dideoxythiocytidine compound. There are two isomers of -D-(+) and -L di (-). Both isomers are highly resistant to HIV. The role of -1. But its -L-(-) isomers have an antagonistic effect on the deamination of cytidine-deoxycytidine deaminase.

Lamivudine is well absorbed orally, with a bioavailability of 72% to 95%, and a plasma half-life of 2 to 4 hours.

Lamivudine has a greater affinity for reverse transcriptase than human DNA polymerase, and thus has a selective effect. Lamivudine has a strong and long-lasting antiviral effect, can improve the body's immune function, and also has an anti-hepatitis B virus effect. Clinically, it can be used alone or in combination with zidovudine to treat patients with advanced HIV infection who have deteriorated.

Lamivudine's bone marrow suppression and peripheral neurotoxicity are smaller than several other nucleoside derivatives, which may be related to its small inhibitory effect on mitochondrial DNA polymerase, but -D- ( +) The bone marrow toxicity of the isomer is 10 times higher than that of the -L-(-) isomer.

Zalcitabine has the same mechanism of action as zidovudine, and is converted into an active triphosphate metabolite in the cell, thereby competitively inhibiting reverse transcriptase activity and possibly stopping the extension of viral DNA. Zalcitabine and zidovudine, when combined, have additive and synergistic antiviral effects, which can effectively inhibit viral replication and disease development.

Zalcitabine can be quickly absorbed by the stomach and intestines, and the bioavailability is 87% to 100%. The blood concentration reaches 1-2 hours after oral administration. Zalcitabine passes through the blood-brain barrier more easily, and 75% of the drug is excreted through the kidney as a prototype. The plasma half-life is 1.2h.

Zalcitabine is mainly used in patients with AIDS and AIDS-related syndromes who cannot tolerate lamivudine treatment. The combination with lamivudine has an additive or synergistic effect on HIV, and can prevent the emergence of drug-resistant virus strains and Reduce toxicity.

2. Ring-opening nucleosides

Ring-opening nucleoside antiviral drugs include acyclovir (Aciclovir) and the like.

Acyclovir (Aciclovir) is a ring-opened guanosine analog, which can be regarded as a purine nuclear analogue that loses C-2 7 and C-3 in the sugar ring. Acyclovir is the first open-loop nucleoside antiviral drug to be marketed. It is a broad-spectrum antiviral drug and is now the drug of choice for anti-herpes virus.

Acyclovir is a white crystalline powder that is slightly soluble in water. The pH of a 5% solution is 11.1. Hydrogen on nitrogen can be made into a steel salt due to its acidity. It is easily soluble in water and can be used for injection.

Aciclovir has a unique mechanism of action, and is only phosphorylated by the virus's thymidine kinase specifically at the position corresponding to the C-5, hydroxyl group into monophosphate or diphosphate nucleoside (in uninfected cells only in infected cells). It is not phosphorylated by cellular thymidine kinase), and then converted into the form of triphosphate in the cell enzyme system, and incorporated into the virus' DNA to play its role in interfering with viral DNA synthesis. Since the compound does not contain a comparable C-3 hydroxyl group, it is a chain stopper, which interrupts the DNA synthesis of the virus.

Acyclovir is widely used in the treatment of herpes keratitis, genital herpes, systemic shingles and herpes encephalitis, and viral hepatitis B. Improper use of acyclovir can cause acute renal failure.

Valaciclovir Hydrochloride is an ester prodrug formed by acyclovir and valine. It is rapidly absorbed orally and quickly converted into acyclovir in the body. Its antiviral effect is acyclovir. Wei played, the mechanism and process of anti-virus is the same as that of acyclovir.

After the oral administration of valacyclovir hydrochloride, it was rapidly absorbed and converted into acyclovir. The peak time of acyclovir in blood was O.88 to 1.75 h, and the oral bioavailability was 67%, which was 3-5 times that of acyclovir. The product is widely distributed after entering the body and can be distributed to a variety of tissues, with the highest concentration in the small intestine, kidney, liver, lymph nodes and skin tissues, and the lowest concentration in brain tissues. Valacyclovir hydrochloride is all converted into acyclovir in vivo.

The antiviral activity of this product is better than acyclovir, and the treatment index for herpes simplex virus type 1 and type 2 is 42.91% and 30.13% higher than acyclovir, respectively, and it is also very high for varicella-zoster virus. The effect is very low, and the toxicity to mammalian host cells is very low.

Ganciclovir has a hydroxymethyl side chain than acyclovir, which can be regarded as a ring-opened deoxyguanosine derivative with a C-3 hydroxyl group and a C-5 hydroxyl group. The effect is stronger than acyclovir and is still effective against acyclovir-resistant herpes simplex virus.

When ganciclovir enters the cell, it is rapidly phosphorylated to form a monophosphate compound, and then converted into a triphosphate compound by the action of cell kinase. In cells infected with cytomegalovirus, the process of ganciclovir phosphorylation is faster than in normal cells. Ganciclovir triphosphate compounds can competitively inhibit DNA polymerases, and can be incorporated into the DNA of human viruses and host cells, thereby inhibiting DNA synthesis. Compounds have a stronger inhibitory effect on viral DNA polymerase than on host cell DNA polymerase.

Ganciclovir is more toxic, the most common being leukocytes and thrombocytopenia. Ganciclovir is clinically used to prevent and treat cytomegalovirus infection in patients with immunodeficiency, such as AIDS patients, tumor patients receiving chemotherapy, and organ transplant patients using immunosuppressants.

Penciclovir is a bioelectronic isosteric derivative of ganciclovir. It is an oxygen atom on the side chain of ganciclovir replaced by a carbon atom. It has the same antiviral spectrum as acyclovir, but biological Low utilization.

In virus-infected cells, penciclovir is phosphorylated by deoxythymidine kinase to penciclovir triphosphate. Triphosphates can inhibit trace venom DNA polymerase, which affects virus replication in cells. The selectivity of penciclovir may come from two reasons. The first is that in normal cells, penciclovir is significantly less phosphorylated than virus-infected cells, so the content of triphosphorylated products in virus-infected cells is significantly higher than in uninfected cells. The affinity of the triphosphorylated product to viral DNA polymerase is significantly higher than that of human DNA polymerase. The structure and mechanism of pentoxilone are similar to other nucleotide analogs. The difference between penciclovir and acyclovir is that the triphosphate activation product of penciclovir exists in cells for a longer time, so the intracellular concentration of penciclovir is higher.

Penciclovir has inhibitory effect on type I and type II herpes simplex virus in vitro. It is clinically used for herpes simplex and genital herpes on the lips or face.

Famciclovir is a diacetate of penciclovir 6-deoxy derivative. It is a prodrug of penciclovir. It is rapidly deacetylated and oxidized to the active penciclovir after absorption in the gut wall after oral administration. Wei, so replace penciclovir.

Famciclovir is rapidly absorbed orally, with a bioavailability of 77%. It is quickly converted to penciclovir in the body, with a half-life of about 2 hours and 60% to 65% excreted by the kidneys. Varicella-zoster virus-infected cells have a longer half-life (9-1Oh), and the intracellular half-life of herpes simplex virus type I and type II infection are 10h and 20h, respectively.

Famciclovir is clinically used to treat shingles and primary genital herpes.

Adefovir dipivoxil is a precursor of adefovir, adefovir is an acyclic analog of 5-monophosphate deoxyaradenosine , and adefovir is adefovir Bis neovaleryloxymethanol ester. Adefovir dipivoxil exerts antiviral effect after being hydrolyzed into adefovir in vivo.

The oral bioavailability of adefovir dipivoxil is about 59%, the peak time is O.58-4.OOh, and the elimination half-life is 7.84h. Adefovir dipivoxil is rapidly metabolized to adefovir 45% after oral administration The combination of glomerular filtration and active tubule secretion is excreted from the urine by the kidney as a prototype.

Adefovir dipivoxil has obvious inhibitory effects on hepadnavirus, retrovirus and acne virus. It is clinically used to treat chronic hepatitis B and can prolong the survival time of patients with advanced AIDS without teratogenicity, mutagenesis, carcinogenesis and embryo toxicity. Adefovir dipivoxil has been approved by the Chinese SFDA for the treatment of chronic hepatitis B, and its indication is adult chronic hepatitis B patients with liver function compensation. This drug is especially suitable for those who need long-term medication or have developed lamivudine resistance.

Antiviral non-nucleosides

The mechanism of action of non-nucleoside reverse transcriptase inhibitors is different from that of nucleoside reverse transcriptase inhibitors such as zidovudine. They do not require phosphorylation activation, and directly bind to the P ester hydrophobic region of the catalytic active site of viral reverse transcriptase, which inactivates the conformation of the enzyme protein, thereby inhibiting the replication of HIV-1. Non-nucleoside reverse transcriptase inhibitors do not inhibit cellular DNA polymerase, so they are less toxic, but they are also prone to resistance.

Medicine. Clinically, non-nucleoside reverse transcriptase inhibitors are usually not used alone, but are used together with nucleoside drugs, which can produce synergistic effects. The main varieties that have been listed are nevirapine and efavirenz.

1. Nevirapine

It is a specific HIV-1 reverse transcriptase inhibitor that does not need to be activated by phosphorylation after entering the cell. Nevirapine blocks RNA-dependent and DNA-dependent DNA polymerase activity by directly linking to the reverse transcriptase of HIV-1 and by breaking the catalytic end of this enzyme, but nevirapine can only inhibit the reverse transcriptase activity of HIV virus. Has no effect.

Nevirapine and nucleoside inhibitors have an additive effect when used in combination. Zidovudine-resistant HIV virus strains are also effective. However, the biggest problem in nevirapine in use is the rapid induction of drug resistance. In vitro tests show that once nevirapine is in contact with the virus, it quickly induces drug resistance, and the sensitivity of the resistant virus strain to nevirapine is 1/400. Clinical trials have also confirmed that nevirapine loses antiviral within 1-2 weeks of administration effect.

Nevirapine can only be used in combination with nucleoside inhibitors to treat patients with advanced HIV infection.

2. Efavirenz

It is a non-nucleoside reverse transcriptase inhibitor of HIV-1. It can non-competitively inhibit HIV-1 reverse transcriptase, and it can inhibit , , , and polymerases of HIV-2 reverse transcriptase and human cell DNA. No inhibitory effect. Efaviron has potent antiviral activity and is also effective against drug-resistant viruses.

Efaviron is well absorbed orally, with a peak time of 3-5 hours. It can easily reach the cerebrospinal fluid through the blood-brain barrier. The concentration can reach IC90 of most wild-type and clinically common strains of HIV-1, including K103N mutant strains.

Clinically, efavirenz is used in combination with other antiviral drugs for combined antiviral treatment of AIDS adults, adolescents and children infected with human immunodeficiency virus HIV-1.

Antiviral protease inhibitor

Human immunodeficiency virus (HIV) protease inhibitors are another class of drugs used to treat AIDS. There are two HIV protein products that are precursors to cleavage of mature proteins. The cleavage process is catalyzed by HIV protease. The released proteins play a decisive role in virus replication. These proteins include the protease itself and reverse transcriptase, integrase and structural proteins. . Among them, the protease is Aspartic Proteinase. One of its characteristics is that it can hydrolyze and break peptide bonds of phenylalanine-proline and tyrosine-proline. It is difficult for mammalian proteases to hydrolyze them. Such drugs are saquinavir, ritonavir, indinavir, and nelfinavir.

1. Saquinavir

It is a polypeptide derivative. It is a highly efficient and highly selective HIV protease inhibitor, cisquinavir, which can inhibit human immunodeficiency virus (HIV) protease, thereby blocking the post-transcriptional modification of viral protease. A drug used to treat HIV infection.

Saquinavir acts in the later stage of HIV reproduction, and the product binds to the activation site of HIV protease, causing it to lose its function of binding and hydrolytically breaking peptides. Saquinavir inhibits HIV protease and other anti-HIV virus drugs, such as azidothymidine, inhibits HIV reverse transcriptase. The target enzyme system is different, and no cross-resistant drug is produced.

The action of saquinavir is competitive and reversible, and its selectivity is high. At concentrations higher than the concentration that inhibits HIV-1 and HIV-2 by nearly ten thousand times, saquinavir is effective against human pepsin, cathepsin D, E and human leukocyte elastase have little inhibitory effect, and have no effect on dipeptidase and propeptidase.

Saquinavir is not completely absorbed orally, its bioavailability is low, and the food can significantly increase the AUC of this product. The blood drug concentration is very low when taken on an empty stomach, and it must be taken within 2 hours after a meal.

Clinically, saquinavir combined with other drugs to treat severe HIV infection can increase the CD4 count and reduce the total amount of HIV in the blood.

2. Indinavir

It is a new type of specific protease inhibitor, which inhibits virus replication by destroying the replication sequence of HIV virus, the inhibition rate is about 99%, and the selectivity for HIV-1 is about 10 times that of HIV-2.

Indinavir is a competitive inhibitor of protease, it can directly bind to the active site of protease, hinder the cleavage of virus precursor polyprotein during the virion maturation process, and the immature virions produced by it are not infectious , Unable to start a new round of infection.

Indinavir is clinically used as a sulfate, which is rapidly absorbed orally, with a peak time of 0.8 h, a relative bioavailability of about 65%, and a elimination half-life of 1.8 h. Indinavir sulfate is excreted by the kidney prototype in less than 20%. Due to the short half-life, it is quickly cleared from the body.

Indinavir is mainly used in adults with HIV-1. Infection, alone is suitable for the treatment of adult patients who are not suitable for clinical use of nucleoside or non-nucleoside reverse transcriptase inhibitors. Indinavir combined with zidovudine treatment group had a significant increase in CD4 cell levels, reduced viral load, and prolonged the survival of patients who progressed to AIDS. Therefore, the combination of indinavir and zidovudine in the treatment of HIV Patients with type 1 infection. This product should not be used in combination with terfenadine, astemizole, triazolam, midazolam and other drugs. In addition, rifampin, a strong inducer of CYP3A4, can not be used in combination with this product because it can reduce the blood concentration of this product.

3. Nefinavir

It is a non-peptide protease inhibitor and acts by reversibly bonding to the active site of the HIV protease. HIV protease is a key enzyme in the replication process of HIV, which can disrupt the mature process of the virus, and then release immature, non-infectious virus molecules.

Nelfinavir in combination with antiviral nucleoside analogs for the treatment of HIV-1 infection in patients with advanced or progressive immunodeficiency. Nelfinavir can inhibit cytochrome P450. Drugs that are mainly metabolized through this pathway can increase the occurrence of side effects when used together with nelfinavir. Drugs that cannot be used at the same time include astemizole, terfenadine, rifampicin, mic Dazolam, triazolam and cisapride.

Other types of antivirals

Other major antiviral drugs used clinically are also beneficial for ribavirin, amantadine hydrochloride, rimantadine hydrochloride, sodium phosphonate and oseltamivir Phos.phate. .

1. Ribavirin

As a broad-spectrum antiviral drug, in vivo and in vitro experiments have shown that it is active against both RNA and DNA viruses and inhibits a variety of viruses such as respiratory syncytial virus, parainfluenza virus, herpes simplex virus, and shingles virus. It can prevent and treat influenza, adenoviral pneumonia, hepatitis A, herpes, and measles caused by influenza A and B viruses. From the perspective of chemical structure, ribavirin can be regarded as an analog of adenosine monophosphate (AMP) and guanosine monophosphate (GMP) biosynthetic precursor aminoimidazolyl nucleoside (AICAR). Ribavirin is susceptible to intracellular purine nucleoside kinase-phosphorylation, followed by triphosphorylation. The obtained ribavirin-phosphate can inhibit hypoxanthine monophosphate (IMP) dehydrogenase, thereby inhibiting the biosynthesis of GMP. Ribavirin triphosphate inhibits 5'-terminal guaninelation of the mRNA and N7 methylation of terminal guanine residues, and competes with GTP and ATP to inhibit RNA polymerase.

Ribavirin can be used to treat measles, chicken pox, mumps, etc. It can also be used to treat upper respiratory tract viral infections by spraying and nasal drops, and intravenously to treat parotid virus pneumonia in children, which have achieved good results. For epidemic hemorrhagic fever, it can significantly shorten the antipyretic time, make urine protein negative, and platelets return to normal. The drug is phosphorylated in the body, and can inhibit viral polymerase and mRNA, as well as prevent pre-AIDS symptoms in people infected with human immunodeficiency virus (HIV).

Ribavirin has a strong teratogenic effect during use, so it is contraindicated in pregnant women and women who are expecting to become pregnant (the product is slowly eliminated in the body, and it cannot be completely removed from the body 4 weeks after stopping the drug). When used in large doses, it can cause heart damage.

2. Amantadine Hydrochloride

It is a symmetrical tricyclic amine, which can inhibit virus particles from penetrating into human host cells, and can also inhibit early replication of the virus and block husking of viral genes and invasion of nucleic acids into host cells.

At a low concentration (0.03-1.0mg / ml), amantadine hydrochloride has a specific inhibitory effect on influenza A virus. As a preventive drug for influenza pandemic population, the protection rate can reach 50% -79%. For example, if it is administered within 48 hours, it can effectively treat the respiratory symptoms caused by influenza A virus. When it is administered within 24 hours, the body temperature can be significantly reduced, and the remaining symptoms can be significantly reduced within 36 hours.

Amantadine hydrochloride is well absorbed orally and can penetrate the blood-brain barrier, causing toxic side effects of the central nervous system, such as headache, insomnia, excitement, and tremor. However, it is less toxic at therapeutic doses. Due to this feature, this product is also used for antitremor paralysis. Amantadine hydrochloride can be secreted in saliva, nasal secretions, and breast milk. About 90% of the drug is excreted as a prototype, mainly from the renal tubules. So far no reports have been found on amantadine hydrochloride metabolites.

Amantadine hydrochloride can effectively prevent and treat all influenza A strains, especially the Asian influenza virus A2 strain.

Amantadine hydrochloride has a narrow antiviral spectrum and is not effective against influenza B virus, rubella virus, measles virus, mumps virus, or herpes simplex virus infection, except for the prevention of influenza A in Asia.

3. Amantadine hydrochloride

It is a derivative of amantadine hydrochloride. Activity against influenza A virus

It is 4-10 times stronger than amantadine hydrochloride and has relatively low side effects on the central nervous system.

Amantadine hydrochloride is quickly and completely absorbed orally. The plasma concentration reached a peak at 3 to 8 hours after administration, and reached a steady state after about 5 days.

Amantadine hydrochloride is extensively metabolized in the liver, and the prototype drug excreted in the urine only accounts for 25% of the dose. The hydroxy metabolites excreted in the urine account for about 18% of the dose, and the excretion in feces is less than 1% of the dose. The average elimination half-life is about 25h.

Amantadine hydrochloride is mainly active against influenza A virus. Inhibition of influenza A virus proliferation in vitro, including H1N1, H2N2, and H3N2 subtypes isolated from humans. In animals infected with influenza A myxovirus, rimantadine hydrochloride has both preventive and therapeutic effects.

Foscarnet Sodium is an organic analog of inorganic pyrophosphate, which can inhibit in vitro tests including cytomegalovirus (CMV), human herpes virus, herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2 ) Etc. Herpes virus replication. Without affecting the concentration of cellular DNA polymerase, sodium phosphonate produces a selective inhibitory effect on the pyrophosphate binding site of virus-specific DNA polymerase, thereby exhibiting antiviral activity.

Sodium phosphonate does not need to be activated (phosphorylated) by thymine kinase or other kinases and is therefore active against HSVTK deletion mutants and CMVUL97 mutants in vitro. Therefore, acyclovir-resistant HSV strain or ganciclovir-resistant CMV strain may be sensitive to sodium phosphonate. However, acyclovir and ganciclovir-resistant mutants with altered DNA polymerase may also be resistant to sodium phosphonate. In in vitro tests, the combination of sodium phosphonate and ganciclovir showed an increased activity.

Sodium phosphonate is mainly used for skin and mucosal infections of herpes virus. This product still has the effect of inhibiting HIV reverse transcriptase, and has been tried on AIDS patients complicated by rhinitis, pneumonia, colitis or esophagitis.

4. Oseltamivir Phosphate

It is a neuraminidase inhibitor of a full-carbon six-membered ring influenza virus. It is an ethyl ester prodrug. It is easily absorbed by the gastrointestinal tract after oral administration. The oral bioavailability can reach 80%. An active substance is produced, thereby producing an activity that inhibits the influenza virus. Oseltamivir has a certain effect on avian influenza virus.

Oseltamivir phosphate is an oral preparation that reduces virus transmission mainly by interfering with virus release from the surface of infected host cells. It is clinically used to prevent and treat influenza caused by influenza A and 8 viruses, and is the most effective medicine for preventing and treating influenza.