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Fighting Human Immune deficiency Virus with HIV Protease inhibitors
HIV protease is a retropesin enzyme that enhances the growth of human immunodeficiency (HIV) that is responsible for causing AIDS. The retropepsin cleaves the newly synthesized polypropteins to create a mature retrovirus that is very infectious. Moreover, it is the HIV protease that dictates the infection rate. In case it remains ineffective, the HIV virions become uninfectious and when it is effective, the HIV virions appear very infectious. Thus, the introduction of an inhibitor to the HIV protease prevents the replication of HIV. Today, most researchers are basing their studies on the use of HIV protease inhibitors in an attempt to curb the human immune deficiency virus.
It is important to examine the structure of the HIV protease and how it functions to help us understand how the inhibitor can influence its normal operations.
HIV Protease Structure
HIV protease occurs as a homodimer that is made up of 99 amino acids in each subunit. The active site that reacts to AIDS is located within the identical subunits. It has similar characteristics as aspartic proteases. The Asp-Thr-Gly residues the reaction process by acting as catalysts. The protease also has molecular flaps that facilitate movement when the enzyme reacts with a substrate. The protease catalyzes the hydrolyzed peptide bonds with high selectivity sequence.
HIV protease inhibitors are the antiretroviral drugs that are currently used in the treatment of HIV infection. The inhibitors act against the human immunodeficiency virus and produce immature non-effective viral particles. It does this by preventing the cleavage of polyproteins in the blood. The most common HIV protease inhibitors include ritonavir, nelfinavir mesylate, saquinavir and indinavir sulfate. They reduce the plasma viral load and increase the CDA4+ cell count which enables the AIDS patients to live longer.
HIV protease inhibitors were invented by pharmaceutical researchers who were working for Abbot Laboratories, Merck Company and La Roche Inc between 1989 and 1994. Their findings were very significant following the prevailing rate of AIDS across the world. The first discovered HIV protease inhibitor was Invirase, also called Saquinavir, that was invented by Joseph A. Martin and Sally Redshaw. After some time, Dale J. Kempf and Hing L. Sham created the HIV protease inhibitor named Norvir in the Abbot Laboratory. In addition, they invented another inhibitor which was named Kaletra and Pentothal. Merck & Company inventors came up with an inhibitor which was named Crixivian. Finally, the Agouron Pharmaceuticals of Japan invented Viracept. However, in 1995 the United States Food and Drug Administration (FDA) approved only HIV protease inhibitors for lowering the virus load in AIDS patients. It is noted that these medications work at the final stage of virus replication and deter HIV from interfering with the protease enzyme by making new copies. The FDA also approved Invirase, Norvir and Crixivian to fight the infectious virions. Antiretroviral therapy (ART) has become the most popular form of treating HIV infection. This involves taking at least two different drug classes. Currently, FDA has approved quite a number of inhibitor drugs. The inhibitors approved include Non-nucleoside Reverse Transcriptase Inhibitors (NNRIs), Nucleoside Reverse Transcriptase Inhibitors(NRTIs), Protease Inhibitors (PIs), Integrase Inhibitors and Fusion Inhibitors.
How HIV protease Inhibitors work
HIV protease inhibitor works by initiating itself with the active site. It binds by adapting to the structure of the substrate in order to disable the enzyme. However, the HIV protease inhibitor may fail to meet its purpose due to high mutation rate of the retroviruses that is caused by few amino acids. Thus, it is necessary to administer drugs that will derail the resistance caused by the virus. The purpose of the HIV protease inhibitors is to arrest the maturation of the nascent infectious virus. Protease is known for cleaving precursor proteins into their final products during the formation of virus particles from the infected cell. However, when the inhibitor is introduced, the proteins required for modifying the virus particles are rendered ineffective thereby preventing the infection of new cells.
HIV protease inhibitors are protein chemicals that aids in the prevention of conversion of HIV particles to infectious cells. They alter adipocyte metabolism and increases lypolysis. As a result, insulin decreases as glucose uptake is hindered. The HIV protease inhibitor consists of the hydroxyethylen scaffold that provides hydrogen that is needed for hydrolysis as it reacts with the enzyme. The hydroxyl group forms a hydrogen bond with the carboxylic acid on the two residues of Asp25 in the binding site. Later, the hydrogen bonds between the water molecules and the carbonyl groups of the peptidomimetic inhibitors combine together at the flap region. The proton acceptor on the nonpeptide inhibitors take the place of the water molecules and reacts with the IIe50 and IIe50’ residues in the enzyme at the flapping point. This increases the potency of the HIV protease inhibitors to accept the hydrophobic amino acids on the naturally existing substrates. Binding energy is increased by high numbers of hydrogen bonds in the protease inhibitor.
Structure of HIV protease inhibitor
Figure2 the structure above indicates how a protease inhibitor binds to the active site of the HIV protease. The blue block shows the central core motif with the hydroxyl group forming hydrogen bonds with Asp-25 and Asp-25´residues, Hydrogen bonds with the carbonyl groups on the inhibitor to the water molecule linked to Ile50 and Ile50´. The pink blocks show the hydrophobic groups and their complementing pockets referred to as S1, S1´, S2 and S2´.
HIV Protease Inhibitors Suppression of the HIV retrovirus and mutation
HIV protease inhibitors have significantly contributed towards the reduction of viral which lowers the plasma HIV RNA after the introduction of the antiretroviral drug to a patient. Monotherapy helps in influencing the life cycle of the infected cells. In a study of Indinavir, CDA+ count of a patient increases as the viral load is reduced by the inhibitor. It is seen that the dose of the drug which is less than 2400 mg daily causes the suppression of the virus for a short time only. However, with the ritonavir 600 mg dose administered twice in a day caused a lasting reduction of viral load. It is worth noting that the sustained suppression of the viral load led to a subsequent sustained increase in the CD4+ count level. Nelfinavir and amprenavir also reacted in the same manner as the ritonavir. Hemorrhage started in patients with higher plasma rates. Today, Monotherapy is not a recommended method because the antiviral may respond for a short duration leading to drug resistance in a patient’s body thereby increasing the chances of infections. Moreover, in some cases the viral load may reduce as the CD4+ count increases when a single protease inhibitor is used. Nevertheless, drug resistance is caused by high plasma viral load as evident in most patients. Thus, it is advisable to stop taking antiretroviral drugs since the patient’s blood cannot support the high dosage of the protease inhibitor.
Killing HIV-infected cells
The infected cells are destroyed by using protease-activated caspases-3 protein that substitutes HIV proteolytic cleavage sites with the endogenous type. This transduces several cells in the active site as it remains inactive in the infected cells. The protease- activated caspase-3 is processed into an active form by HIV protease in the HIV-infected cells. Thus, an apoptosis of the infected cell is formed. The activation of caspase-3 increases the formation of apoptosis that increases the level of caspase-activated DNAse which cause the death of infected cells. However, the emergence of resistant HIV strains poses a threat to this method of reducing infection rate. Caspase-3 helps in prolonging the life of a patient because it deals with the infected cells by destroying them completely. It is noted that the protease inhibitors increase the life span of the infected cells. Caspase-3 reduces the mutation rate of the infected cells by the use of the pathogenic-specific cleavage sites that is helpful in killing infectious diseases that are regulated by the cellular proteases. The reverse transcriptase molecules are packed inside the infected cell and initiate the death of the cell which prevents replication of the virus.
HIV Protease inhibitors help fight AIDS-defining illnesses
The use of the highly active anti-retroviral therapies helps in protecting the patients against apolipoprotein B. The patients may suffer from other chronic diseases such as lipodystrophy and hyperlidemia when the protease inhibitors are used continuously. However, the use of hepatoma cells from both man and rat and the hepatocytes from transgenic mouse can facilitate the prevention of proteasomal degradation of apolipoprotein B. This rat study shows that the treatment of the protease inhibitor reduced the secretion of the apolipoprotein B which forms the greatest component of triglyceride and cholesterol plasma lipoproteins. Nevertheless, the use of oleic acid which normally stimulates neutral-lipid biosynthesis increased the secretion of the apoliprotein B above the optimum point. Thus, a molecular based inhibitor is being investigated to reduce the chances of infections in patients.
Resistance to HIV Inhibitors and resiliency to the resistance
The patients treated with protease inhibitors are likely to suffer more because of the drug resistant virus. This is evident with the limited time taken to respond to the antiretroviral drugs. The accumulation of secondary mutations in virus increases the level of drug resistance. It is noted that single amino acid mutations bear only a small change to the sensitivity of drugs which alters the normal functioning of the patient’s body. Furthermore, the resistance to the protease inhibitors increases the plasma viral loads and the CD4+ cell counts. The persistent administration of one protease inhibitor raises the level of both primary and secondary mutations leading to increased chances of adverse infection. Moreover, the virus resists both the drug and the protease inhibitors administered to the patient. The emergence of resistant virus can be prevented by using drugs that maintain high plasma concentrations. For instance, the regimens for indinavir and nelfinavir are approved today to reduce the production of virus. Thus, the patients are advised to strictly adhere to the prescribed dose in order to increase the concentration of plasma. However, the physicians should consider how the patients respond to the protease inhibitors. This is because some patients have genotypic resistance to drugs due to poor compliance. Poor tolerance to high doses of protease inhibitor may cause death when the antiretroviral drugs are taken. Therefore, they should not use the drugs at all in case of the existence of this compliance. Resistance to drugs can be reduced if the protease inhibitor is combined with two nucleoside analogues. In addition, patients who have good compliance should take combinations of antiretroviral drugs to suppress the resistance of the virus.
The use of the highly active anti-retroviral therapies helps in protecting the patients against apolipoprotein B. The patients may suffer from other chronic diseases such as lipodystrophy and hyperlidemia when the protease inhibitors are used continuously. However, the use of hepatoma cells from both man and rat and the hepatocytes from transgenic mouse can facilitate the prevention of proteasomal degradation of apolipoprotein B. This rat study shows that the treatment of the protease inhibitor reduced the secretion of the apolipoprotein B which forms the greatest component of triglyceride and cholesterol plasma lipoproteins. Nevertheless, the use of oleic acid, which normally stimulates neutral-lipid biosynthesis, increased the secretion of the apoliprotein B above the optimum point. Thus, a molecular based inhibitor is being investigated to reduce the chances of infections in patients.