What is a disease
What is protease
How does a protease inhibitors work
What is a protease inhibitor
Protease Inhibitors and HIV
Protease inhibitors and Rheumatoid Arthritis
Anticancer activity of protease inhibitors
Protease Inhibitors and Herpes
Protease Inhibitors and Disease
Fig. 1 Showing a Diagrammatic Representation of the Enzyme Protease.
A disease is the destruction in the function of a human which leads to specific symptoms which in turn affects specific sites and are not results of physical injury. Protease cleaves longer proteins into shorter core proteins via proteolysis this is the process whereby hydrolysis of the peptide bonds occur that links subsequent amino acids to a polypeptide chain (Kohei Oda 2012). It is therefore crucial for the effectiveness of an infectious virus. Protease Inhibitors bind to the active sites of these proteases which in turn inhibits the passage of the protein from becoming shorter units (virions) in order to remain non-infectious. One such example is seen in the Human Immuno-defiency Virus commonly known HIV. In a video Dr. Rufus Rajadurai extensively explained the invasion process of the HIV virus into the uninfected cell of a human to the point of infection
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Fig. 2 Showing a Diagrammatic Representation of a Virion. Fig.3 Showing a Diagrammatic Representation of a Protease Inhibitor.
A protease inhibitor is therefore a drug used to interfere with the key stage of viral replication and used to stop this fatal process.
The virus fuses with the cell’s plasma membrane. The capsid proteins are removed, releasing the viral proteins and RNA. Reverse transcriptase catalyzes the synthesis of a DNA strand complementary to the viral RNA. Reverse transcriptase catalyzes the synthesis of a second DNA strand complementary to the first. The double-stranded DNA is incorporated as a provirus into the cell’s DNA. Proviral genes are transcribed into RNA molecules, which serve as genomes for the next viral generation and as mRNAs for translation into viral proteins. The viral proteins include capsid proteins and reverse transcriptase (made in the cytosol) and envelope glycoproteins (made in the ER). Vesicles transport the glycoproteins from the ER to the cell’s plasma membrane. Capsids are assembled around viral genomes and reverse transcriptase molecules. New viruses bud off from the host cell.
that the release of new virus particles is inhibited and their spread is hindered. There are two
The overall structure of NoV Pro is that of a cysteine protease with a chymotrypsin-like fold and a catalytic triad consisting of His-30, Glu-54, and Cys-139 (71). The structures of Norovirus proteases share a high degree of structural similarity to picornaviral 3C proteases (75, 76), making picornaviral proteases an excellent model for comparison. The mechanism of catalysis for the Norovirus proteases is similar to the serine proteases that contain a Ser-His-Asp triad in the active site. The mechanism of catalysis of serine proteases is shown in Figure 2. The catalysis reaction occurs in two halves, acylation and deacylation. First, the carbonyl of the peptide substrate is attacked by the Serine and His residues of the catalytic triad (77). The result is the first of two tetrahedral intermediates which collapses to form the acylenzyme intermediate (77). The second half of the reaction is very similar where a water molecule and His residue attack the acylenzyme intermediate to yield the second “transition-state” intermediate which collapses to release the carboxylic acid product (77). Similar to the serine proteases, the Cys-139 residue of Norovirus proteases functions similarly to the Ser residue and the Glu-54 functions as the Asp residue of the serine proteases while the His residue function is
Renin inhibitors are effective in treating hypertension because they block the activity of an enzyme secreted within the kidney called renin. Renin inhibitors blocks the activation of angiostensinogen. Without the activation of angiostensinogen, blood vessels will relax and widen. This will cause a decrease in blood pressure. The blood volume decrease as well through the diuretic and natriuretic effects with helps treat hypertension.
preventing the repair of cancer cell and tumor growth.8 However, This drug is under initial stage
After the anthrax mail attacks in 2001, scientists learnt that once PA was bound to ATR, a protease from the host cells cleaves off the N-terminus of PA [12]. N-terminus is basically amino acid residue on one end of a polypeptide [14]. Anyway, cleaving N-terminus from PA induces a switch that causes PA to activate and bind to six other PAs [12]. With seven of these activated PAs together, they form a heptamer on the host cell [12]. They then bind to either EF or LF and the host cell ingests this new compound in through endocytosis [12]. The endosome formed inside the host cell becomes more acidic, and this changes the shape of the PA molecules within [12]. Consequently, the altered PA molecules form a pore in the endosomal membrane and EF or LF is injected into the host cell’s cytosol where they then become toxins [12].
These proteins can be recognized by B cell antibodies or presented on infected cell surfaces for T cell detection. The proteins undergo disruptive selection as HIV gains all mutations that allow it to survive or overpower the immune system. Many viruses could encode semi-different proteins, leading to diverse strains arising through disruptive selection. The host on the other hand, undergoes directional selection. All cells that cannot survive the virus are eliminated by it. Thereby any cells such as lymphocytes that survive are likely to have similar traits such as the same specificity for the viral antigen. Due to the mutation rate of HIV, the immune system is constantly experiencing this selection. If a cell survived a previous mutation, it might not survive the subsequent one. The cell pool improves its abilities to combat the new strain thanks to the selection against disadvantageous
Protein tyrosine kinase is an enzyme that catalyzes the transfer of the γ phosphate of ATP to tyrosine residues on protein substrates. Phosphorylation of proteins by kinases is an important mechanism in signal transduction and regulating cellular activity, such as cell division. Tyrosine phosphorylation is a key covalent modification that occurs in multicellular organisms as a result of intercellular communication during embryogenesis and maintenance of adult tissues. Phosphorylation of tyrosine residues modulates enzymatic activity and creates binding sites for the recruitment of downstream signaling proteins [2].
The model enzyme as seen in figure 1 has a molecular weight of 1365 g mol-1 and is made up of 24 serine proteases. The active site is only known through X-ray crystallography and because of this knowledge surrounding the mechanism is limited. The crystallography data shows the proposed mechanism involves three main molecules in the active site. These are serine 195, histidine 57 and aspartate 102. They believe the functional groups hold all importance in relation to reaction. The functional groups are a hydroxyl group an imidazolyl group and the carboxylate ion.
the macromolecular synthesis of the host cell is not shut off, and virus purification is difficult
A virus by definition is “any member of a unique class of infectious agents . . . that consists of genetic material, which may be either DNA or RNA, and is surrounded by a protein coat and, in some viruses, by a membrane envelope” (“virus”). Such agents are unable to produce the necessary nutrients to survive because they do not possess the biochemical mechanisms or organelles to synthesize necessary elements. As a result, they feed off a living host cell by attaching to the cell’s docking proteins and injects its virus through the membrane. However, the cycle of a virus is more complex than it may seem.
The fact is that the medications stop new infections by killing the HIV virus before taking control in the body. This conclusion was obtained while investigating the way in which the virus develops
Chickpeas and several types of grains produce protease inhibitors in order to combat herbivory. Protease inhibitors help these plants combat herbivory by preventing their predators from being able to soak up the protein contained within them. Similar to amylase inhibitors, protease inhibitors serve as a method of preventing predators from getting essential nutrients that they need. Consequently, predators will avoid eating these plants, ensuring survival and reproduction of these plants.
The HIV-1 virion is approximately 120 nm in diameter, roughly spherical, and is composed of two copies of a single stranded positive sense RNA enclosed by a capsid (24). The HIV-1 genome is less than 10 kb and encodes for more than nine different gene products. It encodes for 3 major structural protein genes: gag (group-specific antigen), pol (DNA polymerase), and env (Envelope), which code for major structural proteins and essential enzymes. Gag generates the mature Gag protein matrix (MA or p17), capsid (CA or p24), nucleocapsid (NC or p7), and p6, which encompass proteins for the basic infrastructure of the virus such as the inner core of the viral particle (25). Pol encodes for reverse transcriptase (RT), which enables the virus to reproduce, integrase (IN), which is necessary to integrate the viral double stranded DNA into the host genome, RNAse H, and HIV protease, which are all encapsulated in the core of the inner particle formed by the viral capsid protein p24 (25). Env encodes for glycoproteins of the outer membrane such as outer gp120 (which enables the virus to attach and fuse to cells of the host), and transmembrane gp41 that anchors the glycoprotein complex to the surface of the virion (25). Between the core and the envelope is the HIV matrix proteins which are composed of the viral protein p17 (23). HIV-1 also encodes for proteins with important regulatory elements (tat (Trans-Activator of Transcription) and rev
Viruses are biological agents that are extremely small and highly infectious. It possesses the ability in infecting all cell types, from complex eukaryotes such as plants and animals, to microorganisms including archaea and bacteria. [1] However, it could only rely on infecting a host cell for viral replication, which when infecting a host cell it incorporates its genetic materials into the host cell DNA and uses the host’s cellular component for replication, such that the cell produces viral proteins and genetic materials for assembling new viron instead of its usual products. [2]