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Lesson 8: Antivirals Thursday, March 17, 2016 Understandings • Viruses lack a cell structure and so are more difficult to target with drugs than bacteria. • Antiviral drugs may work by altering the cell’s genetic material so that the virus cannot use it to multiply. Alternatively, they may prevent the viruses from multiplying by blocking enzyme activity within the host cell. Applications and Skills • Explanation of the different ways in which antiviral medications work. • Description of how viruses differ from bacteria. • Explanation of how oseltamivir (Tamiflu) and zanamivir (Relenza) work as preventative agents against flu viruses. • Comparison of the structures of oseltamivir and zanamivir. • Discussion of the difficulties associated with solving the AIDS problem. Viruses • Viruses are sub-microscopic and can only be studied with an electron microscope • They come in all shapes and sizes • They are such small and simple structures that there is debate about whether they can be classified as living organisms in their own right. They contain only two viruses. main components, protein and nucleic acid (either RNA or DNA), have no cellular structure, and are only capable of reproducing inside another living cell. Virus Structure • Viruses have a core consisting of their genetic information (carried in the form of either DNA or RNA) which is surrounded by a protein coat known as a capsid. • This capsid consists of identical protein subunits, called capsomeres, and its role is to protect the genetic information in the core. • The capsid and genetic material together are called a nucleocapsid. • Some viruses, such as the human immunodeficiency virus (HIV), also have a lipid envelope that surrounds the nucleocapsid Viruses • Viruses take over the function of another cell, the host-cell, and use that other cell to carry on reproduction How does the body fight back? • The body’s defense system usually responds to viral infections by producing specific antibodies, which act against a virus in the immune response. This often leads to protection, known as immunity, against repeated infections with the same virus. • But sometimes the virus is not completely eradicated from the body and remains dormant in cells. This can cause a flare-up on another occasion, such as some herpes infections which cause cold sores. Viruses Cause Many Deaths • • • • • • • Flu Measles Meningitis Polio HIV Ebola Avian Flu A Difficult Fight • Treating viral infections is particularly difficult because the viruses live within host cells and so cannot be easily targeted. • Antibiotics such as penicillin are effective against bacteria, because they can target a structure such as a cell wall, but there are no equivalent structures to target in viruses. • Another problem is the speed at which viruses can multiply, so that they are often spread through the organism by the time that symptoms appear. • In addition, virus particles have a tendency to mutate rapidly, which means that they make small changes in their genetic material, and this changes their susceptibility to drugs. Vaccines • Vaccines were first introduced in the 18th century, and today are a major aspect of preventative healthcare, known as prophylactic treatment. • Vaccines work by stimulating the body to prepare specific antibodies which can give immunity. Successful vaccination programs have reduced the incidence of diseases such as cholera, polio, and measles. Limitation To Vaccines • Why do we need a flu shot every year? Since viruses mutate so rapidly, vaccines are not always effective forever. • In addition, sometimes our immunity wanes as we age so we need booster shots to ensure continued protection Antiviral Drugs • When vaccines do not exist or are not effective, we must rely on antiviral drugs to treat viral infections Antivirals – How Do They Work? • Some alter the genetic material within cells – once inside a cell, the drug is converted into an active metabolite that becomes incorporated into the growing DNA strand (needed for viral replication) halting its synthesis. An example of a drug that acts in this way is aciclovir (acyclovir), which is used to treat cold sores; it stops viral DNA replication and so stops the virus from multiplying. • Some inhibit the activity of enzymes within the host cell that are necessary for the formation of new viruses. An example is indinavir, which is used in AIDS treatment; it inhibits the HIV enzyme protease, which is essential to the assembly of functional new HIV viruses. • Some stop the viruses from infecting host cells by preventing them from binding to the host cell surface and gaining access into the cell. Some drugs used to treat AIDS work in this way. • Some prevent the virus from leaving the host cell so that it cannot infect other cells – see oseltamivir and zanamivir below. Lesson 9: Influenza Friday, March 18, 2016 Influenza • We usually do not think of getting the flu as a death sentence but roughly half a million people each year die of the flu • Infectious disease doctors are constantly on the lookout for the mutation that will cause a pandemic – a global outbreak with a high risk of casualties Influenza A and B • Flu is causes by two different types of viruses – influenza A and B • They are spherical viruses and have RNA as their genetic material. • Flu viruses have specific proteins on their surface, of which two play a key role in their life cycle. Flu Proteins • 1 Hemagglutinin (H) is a glycoprotein that enables the viral particle to ‘dock’ with the host cell before it enters. • 2 Neuraminidase (N) is an enzyme that catalyses a cleavage reaction which allows the new viral particles to escape from the host cell and spread infection. The enzyme snips off a type of sugar molecule, sialic acid, from glycoproteins on the surface of the host cell membrane. Attacking Flu • If the action of either of these viral proteins was affected, it would evidently interrupt the viral life cycle. Of the two, neuraminidase seems to be a better target for drug design and so it has become a focus for research. • Neuraminidase binds to its reactant sialic acid, the substrate, at a specific region known as the active site. It is this binding between enzyme and substrate that gives the catalytic action, as it provides a reaction pathway of lower activation energy. Chemicals that interfere with this binding are called inhibitors and usually have a specific with the enzyme. Tamiflu Action • https://www.youtube.com/watch?v=0qCTyKrh VWc&feature=youtu.be New Drugs • The three-dimensional structure of neuraminidase became known through X-ray crystallography in 1993, including details on its active site. This enabled researchers to design a molecule which could bind at the active site and so block the binding of substrate and act as an inhibitor. • The first neuraminidase inhibitors were designed by a team in Australia, and led to the production of zanamivir (Relenza), which was approved for use in 2000. It was closely followed by the production of oseltamivir (Tami u). Sialic Acid Lesson 10: HIV/AIDS Monday, March 21, 2016 HIV/Aids • https://www.youtube.com/watch?v=oYwtMor ZbdY • http://www.pbs.org/wgbh/pages/frontline/vi deo/flv/generic.html?s=frol02s461q6b&contin uous=1 HIV/AIDS • AIDS was first recognized in 1981 and was found to be caused by the HIV virus a few years later. • There are now believed to be more than 34 million people infected with HIV worldwide, and approximately 2 million deaths occur each year from AIDS. HIV • HIV primarily infects vital white blood cells in the immune system. These cells are called CD4+ T cells. • The virus binds to specific receptor proteins on the cell surface and then penetrates the cell. • HIV is a retrovirus, which means that its genetic material is in the form of RNA rather than DNA. • The virus releases its RNA into the cell and the enzyme reverse transcriptase controls the synthesis of viral DNA from this RNA. The viral DNA integrates into the cell’s own DNA and replicates with it when the cell divides. Viral particles are produced within the host cell, and are released in large numbers when the cell dies. Why is HIV Hard To Combat? 1. The virus destroys helper T cells, the very cells in the immune system that should be defending the body against the virus. 2. The virus tends to mutate very rapidly, even within a patient. It is thought that there is more variation in HIV in a single patient than in the influenza virus worldwide in a year. These variations mean that the virus ‘escapes’ the immune response, so the patient has to make a response to the new virus. 3. The virus often lies dormant within host cells, so the immune system has nothing to respond to. Antiretrovirals (ARVs) • Antiretroviral drugs target and interrupt the following different stages in the HIV life cycle: – binding and fusion of the virus to the receptor on the CD4 cell membrane – reverse transcription of viral RNA to DNA in the host cell – integration of viral DNA into the host chromosome – release of new viral particles by budding from the host cell surface. How AZT Works • http://www.hhmi.org/biointeractive/aztblocks-reverse-transcriptase Triple Cocktail • Of these targets, inhibitors of the viral enzyme reverse transcriptase are the most widespread. They include drugs such as AZT, also known as zidovudine, which was the first antiretroviral drug to be approved. • It has been found that the best results occur when a combination of different ARVs is used. Combination treatments typically include two different reverse transcriptase inhibitors plus a third drug, all of which can be taken as a single pill once daily. This regimen has been referred to as the “triple cocktail.” • The cost for most combination treatments is approximately $12,000 per patient per year. AIDs Vaccine Intense research on developing a vaccine for HIV/AIDS is ongoing. There are some hopes that a therapeutic vaccine may be possible to help control the infection in people who are HIV-positive. But the development of a preventative vaccine that would give immunity to people who are HIVnegative has so far not been possible. This is mainly because of the problem of the variable nature of the virus within cells, and the fact that the immune response seems to act too slowly in the case of HIV infection. • Truveda To date, the only prophylactic treatment for the prevention of HIV infection in high-risk individuals is Truveda • Truveda is a fixed-dose combination of two antiretroviral drugs used for the treatment of HIV/AIDS. • In studies, tenofovir reduced the incidence of HIV infection, especially in high-risk individuals but produced conflicting results in other studies. One study estimated through mathematical modeling that daily intake of Truvada could potentially achieve a 99% of risk reduction of contracting HIV in high risk individuals. Another study, iPrEX OLE, showed overall PrEP effectiveness of 50% rising to 100% when participants took the drug four or more times per week. A Cochrane review found that both tenofovir alone, as well as the tenofovir/emtricitabine combination, decreased the risk of contracting HIV by 51%. • In conclusion, PrEP has not been shown to make HIV 100% nontransmittable and is currently only recommended for high risk individuals HOMEWORK • Please review your notes on nuclear chemistry from Regents, particularly writing nuclear equations and calculating half-life • I am not going to reteach this material in the interest of time Questions Answers