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Antiviral drugs. Pharmaceutical chemistry. Assist . Prof . Karima F. Ali Al-Mustansiriyah university College of pharmacy. The classification and biochemistry of viruses
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Antiviral drugs Pharmaceutical chemistry Assist . Prof . Karima F. Ali Al-Mustansiriyah university College of pharmacy
The classification and biochemistry of viruses Viruses are unique organisms. They are the smallest of all self-replicating organisms, able to pass through filters that retain the smallest bacteria. The simplest viruses contain a small amount of DNA or RNA surrounded by an uncomplicated protein coat. Some of the more complex viruses have a lipid bilayer membrane surrounding the nucleic acid. Viruses must replicate in living cells, which has led many to argue that viruses are not even living organisms but that they somehow exist at the interface of the living and the nonliving.
The most basic requirement is for the virus to induce changes in the host cell, so that viral genes are replicated and viral proteins are expressed. This will result in the formation of new viruses, usually many more than the number that infected the cell initially. The virus turns the biochemical systems of the host cell to its own purposes, completely subverting the infected cell. An infection that results in the production of more viruses than initiation of infection is called a productive infection.
A typical DNA virus will enter the nucleus of the host cell, where viral DNA is transcribed into messenger RNA (mRNA) by host cell RNA polymerase. mRNA is then translated into virus-specific proteins that facilitate assembly, maturation, and release of newly formed virus into surrounding tissues. RNA viruses are somewhat different, in that their replication relies on enzymes in the virus itself to synthesize mRNA. An adult virus possesses only one type of nucleic acid (either a DNA or an RNA genome). Another unique feature of viruses is that their organized structure is completely lost during replication within the host cell; the nucleic acid and proteins exist dispersed in the cytoplasm.
Classification of viruses Viruses are classified on the basis of several features: • Nucleic acid content (DNA or RNA) • Viral morphology (helical, icosahedral) • Site of replication in cell (cytoplasm or nucleus) • Coating (enveloped or non enveloped) • Serological typing (antigenic signatures) • Cell types infected (B lymphocytes, T lymphocytes, monocytes)
The infectious process for a virus The process of viral infection can be sequenced in seven stages: 1. Adsorption, attachment of the virus to specific receptors on the surface of the host cells, a specific recognition process. 2. Entry, penetration of the virus into the cell. 3. Uncoating, release of viral nucleic acid from the protein coat. 4. Transcription, production of viral mRNA from the viral genome. 5. Translation, synthesis of viral proteins (coat proteins and enzymes for replication) and viral nucleic acid (i.e., the parental genome or complimentary strand).
6. Assembly of the viral particle. New viral coat proteins assemble into capsids (the protein envelope that surrounds nucleic acid and associated molecules in the core) and viral genomes. 7. Release of the mature virus from the cell by budding from the cell membrane or rupture of the cell and repeat of the process, from cell to cell or individual to individual
This channel is required for the fusion of the viral membrane with the cell membrane. b) Rising the pH of the endosome (an acidic pH inside the endosome is required for viral uncoating) this induced conformational changes in the hemagglutinin during its intracellular transport at a later stage. The conformational changes in hemagglutinin prevent transfer of the nascent virus particles to the cell membrane for exocytosis. Rimantadine is generally 4 to 10 times more active than amantadine. Antiviral spectrum -Influenza A virus (not B and C virus)
The influenza virus contains the surface proteins neuraminidase, hemagglutinin, and M2, which play key roles in infection and spread of the virus from cell to cell.
Other effects -Amantadine has anti parkinsonian effects. The mechanism of action is not clear but it may be related to: a) the anti muscarinic properties of the drug b) the stimulation of the synthesis and release of dopamine (and other catecholamines)
Neuraminidase inhibitors: Zanamivir and Oseltamivir: Protein coat of the influenza virus is a lipid envelope. Two macromolecules, surface glycoproteins, are embedded in the lipid envelope: hemagglutinin and neuraminidase. In order to spread in the body, the flu virus first uses hemagglutinin, to bind to the healthy cell's receptors. Once it has inserted its RNA and replicated, the virus uses an enzyme, called neuraminidase, to sever the connection and move on to the next healthy cell. Hemagglutinin is important for binding of the virus to the host cell membrane by a terminal sialic acid residue. Neuraminidase is an enzyme.
Neuraminidase is believed to be a sialidase, cleaving a bond between a terminal sialic acid unit and a sugar on the surface of the cell, facilitating entry into the cell via endocytosis.
This action is important in enhancing the penetration of viruses into host cells, and hence enhances the infectivity of the virus. If the sialic acid–sugar bond is prevented from being cleaved, the viruses tend to aggregate and the migration of viruses into host cells is inhibited. Hence, drugs that inhibit neuraminidase should be useful in interfering with infection caused by influenza virus type A and B.. The importance of neuraminidase in the infectivity of influenza types A and B suggests that it should be a good target for the development of antiviral drugs. Indeed, neuraminidase inhibitors are clinically useful agents in blocking the spread of the viruses.
The transition state of sialic acid cleavage is believed to proceed through a stabilized carbonium ion. Drug molecules that have been developed strongly resemble the transition state. The first of these, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid, is a highly active neuraminidase inhibitor but it is not specific for the viral enzyme. This compound has served as a starting point for the development for virus-specific agents.
2-deoxy-2,3-dehydro-acetylneuraminic acid sialic acid
Zanamivir is identical to 2-deoxy-2,3-dehydro-N-acetylneuraminic acid except that it possesses a guanidino group at position 4 instead of a hydroxyl group. At positions 119 and 227 of the receptor site, there exist glutamic acid residues. Zanamivir has been shown to form a salt bridge with the guanidine and Glu-119and a charge transfer interaction with Glu-227. These interactions increase the interaction strength with the enzyme and create an excellent competitive inhibitor and an effective antiviral agent for influenza types A and B. 2-deoxy-2,3-dehydro-N-acetylneuraminic acid is a highly active neuraminidase inhibitor but it is not specific for the viral enzyme.
The x-ray crystal structures of neuraminidase and the viral receptor site showed clearly that additional binding sites exist for the C-5 acetamido carbonyl group and the arginine residue at position 152 of the receptor site. In addition, the C-2 carboxyl group of sialic acid binds to Arg 118, Arg 292, and Arg 371. Position C-6 is capable of undergoing a hydrophobic interaction with various amino acids, including Glu, Ala, Arg, and Ile. Maximum binding to neuraminidase occurs when the C-6 substituent is substituted with a non polar chain. In oseltamivir, this non polar group is 3-pentyl. An important feature of oseltamivir is the ethyl ester, which makes the drug orally efficacious Oseltamivir
An important feature of oseltamivir is the ethyl ester, which makes the drug orally efficacious. Oseltamivir is actually a prodrug in its ethyl ester form. Ester hydrolysis releases the active oseltamivir molecules
RTP inhibits viral RNA polymerases. It also prevents the end capping of viral mRNA by inhibiting guanyl-N- Methyl transferase. A marked reduction of intracellular guanosine triphosphate pools and inhibition of viral RNA and protein synthesis.Ribavirin inhibits the replication of a very wide variety of RNA and DNA viruses, Emergence of viral resistance to ribavirin has not been documented
-The analog inhibits viral DNA-polymerase. viruses are inhibited -The triphosphorylated drug is also incorporated into viral DNA, where it acts as a chain terminator. Because it has no 3-hydroxyl group, no 3,5-phosphodiester bond can form. This mechanism is essentially a suicide inhibition because the terminated DNA template containing acyclovir as a ligand binds to, and irreversibly inactivates, DNA polymerase. -Only actively replicating viruses are inhibited
. The ability of idoxuridylic acid to substitute for deoxythymidylic acid in the synthesis of DNA may be a result of the similar van derWaals radii of iodine (2.15 Å) and the thymidine methyl group (2.00 Å). Trifluridine possesses a trifluoromethyl group instead of an iodine atom at the 5- position of the pyrimidine ring. The van der Waals radius of the trifluoromethyl group is 2.44 Å, somewhat larger than that of the iodine atom.
Cytarabine Cytarabine is a pyrimidine nucleoside drug that is related to idoxuridine. This agent is primarily used as an anticancer agent for Burkitt lymphoma and myeloid and lymphatic leukemias. Cytarabine blocks the cellular utilization of deoxycytidine, hence inhibiting the replication of viral DNA. Before it becomes active, the drug is converted to monophosphates, diphosphates, and triphosphates, which block DNA polymerase and the C-2 reductase that converts cytidine diphosphate into the deoxy derivative. Cytarabine is usually administered topically.
The 3-azido group prevents formation of a 5,3 phospho- diester bond, so AZT causes DNA chain termination, yielding an incomplete proviral DNA. Viral DNA-polymerases are more sensitive to this inhibition than are mammalian polymerases . Antiviral spectrum and resistance -Antiviral spectrum includes HIV-1, HIV-2, HTLV-1 and other retroviruses. -Highly resistant mutants have been recovered from many AIDS patients treated for more than 6 months
. Zidovudine
Non nucleoside Reverse Transcriptase Inhibitors: Unlike the nucleoside anti metabolites, the NNRTIs do not require bioactivation by kinases to yield phosphate esters. They are not incorporated into the growing DNA chain. Instead, they bind to an allosteric site that is distinct from the substrate (nucleoside triphosphate)-binding site of RT. Such binding distorts the enzyme, so that it cannot form the enzyme–substrate complex at its normal rate, and once formed, the complex does not decompose at the normal rate to yield products.
Delavirdine Nevirapine
