Antiviral Drugs

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     1  Antiviral Drugs
     2  General Characteristics of Viruses Depending on one's viewpoint, viruses may be regarded as exceptionally complex aggregations of nonliving chemicals or as exceptionally simple living microbes. Viruses contain a single type of nucleic acid (DNA or RNA) and a protein coat, sometimes enclosed by an envelope composed of lipids, proteins, and carbohydrates. Viruses are obligatory intracellular parasites. They multiply by using the host cell's synthesizing machinery to cause the synthesis of specialized elements that can transfer the viral nucleic acid to other cells.
     3  Host Range Host range refers to the spectrum of host cells in which a virus can multiply. (narrow vs. broad) Most viruses infect only specific types of cells in one host species, so they do not generally cross species barriers. Host range is determined by the specific attachment site on the host cell's surface and the availability of host cellular factors.
     4  Viral Structure A virion is a complete, fully developed viral particle composed of nucleic acid surrounded by a coat. Helical viruses (for example, Ebola virus) resemble long rods and their capsids are hollow cylinders surrounding the nucleic acid. Polyhedral viruses (for example, adenovirus) are many-sided. Usually the capsid is an icosahedron. Enveloped viruses are covered by an envelope and are roughly spherical but highly pleomorphic (for example, Poxvirus). There are also enveloped helical viruses (for example, Influenzavirus) and enveloped polyhedral viruses (for example, Herpesvirus). Pleomorphic: Many-formed. A tumor may be pleomorphic. Complex viruses have complex structures. For example, many bacteriophages have a polyhedral capsid with a helical tail attached. Bacteriophage: A virus that infects and lyses certain bacteria.
     5  Schematic of Influenza Virus
     8  Nucleic Acid Viruses contain either DNA or RNA, never both, and the nucleic acid may be single- or double-stranded, linear or circular, or divided into several separate molecules. The proportion of nucleic acid in relation to protein in viruses ranges from about 1% to about 50%.
     9  DNA viruses gene expression is much like that of the host cell DNA-dependent RNA polymerase synthesizes mRNA Host cell ribosomes and tRNAs used to translate viral mRNA Unique viral proteins include structural proteins and replication enzymes for viral DNA. Example-Herpesvirus, Epstein-Barr (mononucleosis)
     10  RNA viruses Cells cannot make copies of RNA. Three kinds of strategies for RNA viruses:
     11  Positive -strand RNA viruses the genome is also a mRNA The first task of the virus is to translate viral-specific proteins including RNA-dependent RNA polymerase (viral transciption/repliction enzyme) from viral RNA. The enzyme makes more mRNA and new RNA for viruses.
     12  Positive-stranded RNA: genome is a molecule of single-stranded "sense" RNA Examples polioviruses rhinoviruses (frequent cause of the common "cold") coronaviruses (includes the agent of Severe Acute Respiratory Syndrome (SARS) rubella (causes "German" measles) yellow fever virus West Nile virus dengue fever viruses equine encephalitis viruses hepatitis A ("infectious hepatitis") and hepatitis C viruses tobacco mosaic virus (TMV)
     13  Negative-strand RNA viruses the genome is the complement of mRNA First task of the virus is to make mRNA. Therefore, the virus imports RNA polymerase or transcriptase as a part of the virus structure.
     14  Negative-stranded RNA viruses: genome consists of one or more molecules of single-stranded "antisense" RNA Examples measles mumps respiratory syncytial virus (RSV), parainfluenza viruses (PIV), and human metapneumovirus. (In the U.S., these close relatives account for hundreds of thousands of hospital visits each year, mostly by children.) rabies Ebola influenza
     15  Retroviruses Virus has the enzyme reverse transcriptase as a part of the viral structure. A double-stranded DNA copy of the viral genome is produced. This copy can integrate into the host cell chromosome. Some retroviruses can cause tumors in animals: oncogenes Human immunodeficiency virus (HIV) is a retrovirus. This is the causative agent of AIDS.
     18  Capsid and Envelope The protein coat surrounding the nucleic acid of a virus is called the capsid. The capsid is composed of subunits, capsomeres, which can be a single type of protein or several types. The capsid of some viruses is enclosed by an envelope consisting of lipids, proteins, and carbohydrates. Some envelopes are covered with carbohydrate-protein complexes called spikes.
     19  Viruses and Cancer The earliest relationship between cancer and viruses was demonstrated in the early 1900s, when chicken leukemia and chicken sarcoma were transferred to healthy animals by cell-free filtrates. Transformation of Normal Cells into Tumor Cells: When activated, oncogenes transform normal cells into cancerous cells. Viruses capable of producing tumors are called oncogenic viruses. Several DNA viruses and retroviruses are oncogenic. The genetic material of oncogenic viruses becomes integrated into the host cell's DNA. Transformed cells lose contact inhibition, contain virus-specific antigens (TSTA and T antigen), exhibit chromosomal abnormalities, and can produce tumors when injected into susceptible animals.
     20  Causes of the Common Cold More than 200 different viruses are known to cause the symptoms of the common cold. Some, such as the rhinoviruses, seldom produce serious illnesses. Others, such as parainfluenza and respiratory syncytial virus, produce mild infections in adults but can precipitate severe lower respiratory infections in young children. Rhinoviruses (from the Greek rhin, meaning "nose") cause an estimated 30 to 35 percent of all adult colds, and are most active in early fall, spring, and summer. More than 110 distinct rhinovirus types have been identified. These agents grow best at temperatures of about 91 degrees Fahrenheit, the temperature inside the human nose. Scientists think coronaviruses cause a large percentage of all adult colds. They bring on colds primarily in the winter and early spring. Of the more than 30 kinds, three or four infect humans. The importance of coronaviruses as a cause of colds is hard to assess because, unlike rhinoviruses, they are difficult to grow in the laboratory. Approximately 10 to 15 percent of adult colds are caused by viruses also responsible for other, more severe illnesses: adenoviruses, coxsackieviruses, echoviruses, orthomyxoviruses (including influenza A and B viruses, which cause flu), paramyxoviruses (including several parainfluenza viruses), respiratory syncytial virus, and enteroviruses. The causes of 30 to 50 percent of adult colds, presumed to be viral, remain unidentified. The same viruses that produce colds in adults appear to cause colds in children. The relative importance of various viruses in pediatric colds, however, is unclear because it's difficult to isolate the precise cause of symptoms in studies of children with colds.
     22  Influenza Influenza is a disease caused by a member of the Orthomyxoviridae. Many features are common with those of the paramyxovirus infections of the respiratory tract.
     23  CLINICAL FEATURES Influenza is characterized by fever, myalgia, headache and pharyngitis. In addition there may be cough and in severe cases, prostration. There is usually not coryza (runny nose) which characterizes common cold infections. Infection may be very mild, even asymptomatic, moderate or very severe.
     24  Source The reservoir is acute infection in other human beings. Spread Is rapid via aerial droplets and fomites with inhalation into the pharynx or lower respiratory tract. Incubation Is short: 1-3 days. Rapid spread leads to epidemics
     25  Complications Tend to occur in the young, elderly, and persons with chronic cardio-pulmonary diseases Consist of:? 1. Pneumonia caused by influenza itself; Pneumonia: an inflammatory condition of the lungs in which they become obstructed with fluid, causing difficult breathing and possibly suffocation. Pneumonia may be caused by bacteria, viruses, fungi, or chemical agents. 2. Pneumonia caused by bacteria- Haemophilus influenzae- Staphylococcus aureus- Streptococcus pneuminiae 3. Other viral superinfection, eg. Adenovirus.Overall death rates increase in times of influenza epidemics.
     26  The virion is generally rounded but may be long and filamentous.A single-stranded RNA genome is closely associated with a helical nucleoprotein (NP), and is present in eight separate segments of ribonucleoprotein (RNP), each of which has to be present for successful replication. The segmented genome is enclosed within an outer lipoprotein envelope. An antigenic protein called the matrix protein (MP 1) lines the inside of the envelope and and is chemically bound to the RNP. The envelope carries two types of protruding spikes. One is a box-shaped protein, called the neuraminidase (NA) (pink rectangles on the surface), of which there are nine major antigenic types, and which has enzymic properties as the name implies.
     27  The other type of envelope spike is a trimeric protein called the haemagglutinin (HA) (illustrated on the left)of which there are 13 major antigenic types. The haemagglutinin functions during attachment of the virus particle to the cell membrane, and can combine with specific receptors on a variety of cells including red blood cells.The lipoprotein envelope makes the virion rather labile - susceptible to heat, drying, detergents and solvents. Haemagglutinin: A substance, such as an antibody, that causes agglutination of red blood cells. Agglutination: The clumping together of red blood cells or bacteria.
     28  The Life Cycle of Influenza Virus Receptor-bound viruses are taken into the cell by endocytosis. In the low pH environment of the endosome, RNP is released from MP1, and the viral lipoprotein envelope fuses with the lipid-bilayer of the vesicle, releasing viral RNP into the cell cytoplasm, from where it is transported into the nucleus. New viral proteins are translated from transcribed messenger RNA (mRNA). New viral RNA is encased in the capsid protein, and together with new matrix protein is then transported to sites at the cell surface where envelope haemagglutinin and neuraminadase components have been incorporated into the cell membrane. Progeny virions are formed and released by budding. The cell does not die (at least not initially).
     29  Flu is one of a rare few viruses that has its genome in separate segments (eight). - This increases the potential for recombinants to form (by interchange of gene segments if two different viruses infect the same cell), and may contribute to the rapid development of new flu strains in nature - can also be duplicated in the laboratory (used for making vaccine strains). Avian and human strains recombining in pigs in the Far East may permit virulent human strains to evolve.
     31  CLASSIFICATION of virus STRAINSIs done on the basis of antigenicity of NP (nucleoprotein) and MP (matrix protein) into three main groups: Influenza A -HA undergoes minor and occasional major changes - very important.- NA some variation.Influenza B) Undergoes relatively slow change in HA with time. Known only in man.Influenza C) Uncommon strain, known only in man.
     32  Nomenclature of Viruses
     33  Influenza A virus is essentially an avian virus that has "recently" crossed into mammals. Birds have the greatest number and range of influenza strains. Avian haemagglutinins sometimes appear in pig human and horse influenza strains. Every now and then (10 - 15 years) a major new pandemic strain appears in man, with a totally new HA and sometimes a new NA as well (antigenic shift). This variant causes a major epidemic around the world (pandemic). Over the subsequent years this strain undergoes minor changes (antigenic drift) every two to three years, probably driven by selective antibody pressure in the populations of humans infected. Epidemiology
     34  Influenza A Evolution 1874 --- (H3N8) 1890 --- (H2N2) .........................Pandemic 1902 --- (H3N2) 1918 --- (H1N1)..........................Pandemic 1933 --- (H1N1)..........................First strains isolated 1947 --- (H1N1)..........................Variation detected 1957 --- (H2N2).........................."Asian" Flu pandemic 1968 --- (H3N2).........................."Hong Kong" Flu pandemic 1976 --- (H1N1).........................."Swine" Flu, non-epidemic 1977 --- (H1N1) + (H3N2)........."Russian" Flu epidemic
     35  Camp Devens is near Boston, and has about 50,000 men, or did have before this epidemic broke loose. It also has the Base Hospital for the Div. of the N. East. This epidemic started about four weeks ago, and has developed so rapidly that the camp is demoralized and all ordinary work is held up till it has passed. All assembleges of soldiers taboo.These men start with what appears to be an ordinary attack of LaGrippe or Influenza, and when brought to the Hosp. they very rapidly develop the most viscous type of Pneumonia that has ever been seen. Two hours after admission they have the Mahogany spots over the cheek bones, and a few hours later you can begin to see the Cyanosis extending from their ears and spreading all over the face, until it is hard to distinguish the coloured men from the white. It is only a matter of a few hours then until death comes, and it is simply a struggle for air until they suffocate. It is horrible. One can stand it to see one, two or twenty men die, but to see these poor devils dropping like flies sort of gets on your nerves. We have been averaging about 100 deaths per day, and still keeping it up. There is no doubt in my mind that there is a new mixed infection here, but what I dont know. Copy of original letter found in Detroit in 1959 Camp Devens, Mass.Surgical Ward No 1629 September 1918(Base Hospital)
     37  This constant antigenic change down the years means that new vaccines have to be made on a regular basis. New influenza strains spread rapidly in children in schools and in places where people crowd together. Influenza epidemics may cause economically significant absenteeism.
     39  Anti-influenza Agents Amantadine · Oseltamivir · Peramivir · Rimantadine · Zanamivir Anti-herpesvirus agents   Aciclovir · Cidofovir · Docosanol · Famciclovir · Foscarnet · Fomivirsen · Ganciclovir · Idoxuridine · Penciclovir · Trifluridine · Tromantadine · Valaciclovir · Valganciclovir · Vidarabine Antiretroviral Agents  NRTIsZidovudine · Didanosine · Stavudine · Zalcitabine · Lamivudine · Abacavir · Tenofovir NNTI’s Nevirapine · Efavirenz · Delavirdine PIsSaquinavir · Indinavir · Atazanavir · Ritonavir · Nelfinavir · Amprenavir · Lopinavir · Tipranavir Other antiviral agents Fomivirsen · Enfuvirtide · Imiquimod · Interferon · Ribavirin · Viramidine
     40  The final stage in the life cycle of a virus is the release of completed viruses from the host cell, and this step has also been targeted by antiviral drug developers. Two drugs named zanamivir and oseltamivir that have been recently introduced to treat influenza prevent the release of viral particles by blocking a molecule named neuraminidase that is found on the surface of flu viruses, and also seems to be constant across a wide range of flu strains.
     41  Both these drugs are effective against the known strains of H5N1 in mouse models although Tamiflu has been disappointing in recent real world use in human H5N1 infection due to 1. delays in treatment and 2. the emergence of resistance. Relenza has not yet been tried in human H5N1 infection. Most attention has been given to oseltamivir (Tamiflu) because it is a tablet, which is easy to administer. Zanamavir (relenza) is administered as a dry powder inhaler much like some asthma inhalers. An intravenous version of Relenza has been administered to volunteers under study conditions but it is not yet approved or in production. Both drugs can be used to treat influenza; they are also both approved for the prevention of influenza. These drugs are also effective against all strains of influenza A, unlike vaccines which are specific only to the strain for which they were designed. Both medications are well tolerated with few side effects, although there is concern over the possibility of psychological effects of Tamiflu and there may be occasional problems with asthmatics who use Relenza. Neuraminidase inhibitors must be taken within 48 hours—preferably within 36 hours—of the onset of flu symptoms. They do not ‘kill’ the flu virus but merely slow the virus replication down to a level where the immune system can more easily destroy it. Thus they can reduce the severity and duration of a flu illn