Antiviral Drugs Lecture Notes PDF 2024-2025

Block 1.2 lectures 2024-2025 lecture Highlighter key Writer Reviewer...

Block 1.2 lectures 2024-2025 lecture Highlighter key Writer Reviewer Doctor explanation Abbreviation Key information Book >> >> Hadi Albin Ahmed Fatimah ALMUTAWA 221-222-223 notes References Student explaintion Deleted Antiviral Drugs Dr.Girish Meravanige College of Medicine, KFU  Overview Viruses: Tiny microscopic infectious Agent that grow and multiple inside the living host cell. Antiviral drugs: Medications which help the body fight against harmful viruses that cause disease. Viruses are classified based on their nucleic acid: 1- DNA viruses (ex: herpes small box, adeno) 2- RNA viruses (ex: influenzas, measles, mumbs,HIV virus) Importance of antiviral drug: Do we have antiviral drugs for most viral infection? -Controlling the severity of viruses, and symptoms. Unfortunately no, we don’t have antiviral drugs for most -Controlling the duration of viruses, and symptoms. viral infections, because there are some viruses which are self limiting, it means after a period of time they will -Prevent viruses from spreading. disappear such as the flu, and common cold. -They control the mortality and morbidity rates. Also, we have some antiviral drugs to treat chronic life- threatening infection like hepatitis, HIV, and herpes. -Boost our immune system so the body can fight against these viruses  Overview of Viral Infections There are many viruses that target different organs in the body. For example, the liver, like hepatitis viruses; the brain, like the meningitis virus; and the immune system, like HIV. Therefore, the targeted organs vary depending on the type of virus.  Learning objectives 1.Why is it so difficult to develop antiviral drugs? 2. Targets for Antiviral drugs ? 3. Basis of Antiviral therapy against Herpes viruses ? 4.What is HAART with HIV infections? 5.Why does combination therapy work better with HIV infections than monotherapy? 6.What are Neuraminidase inhibitors that are used in Influenza infections? 7.What is the basis of Interferon therapy for Hepatitis C ?  Antiviral drugs Antiviral drugs are targeted towards viral encoded enzymes or structures of virus that are important for replication Antiviral drugs are made according to specific unique binding sites in viruses, proteins, and their nucleic acid material, They target specific proteins like structural proteins or functional proteins which are important for the viral replication process, those proteins are being targeted so that we can be able to control the replication, viral surface proteins or maybe viral attachment proteins like those help in integration with the host. Antiviral drugs are available for viruses which cause significant morbidity and mortality Morbidity means person who is suffering with the diseases. Mortality is deaths caused by disease. It is difficult for the antiviral drugs to inhibit viral replication without harming the host cell Antiviral drugs difficultly inhibit the viral replication, or the host cell Once the virus infect the host cell it become integrated with the host genome The drug need get inside these contents that helps the virus to virus infected cell and act on the process that are essential for the normal functioning of the human cellular develop, (it makes sense, cause viral body this is often result in damaging our human cell and causing serious side affects of the drug this why replicate inside the cells so not all more staff having morbidity and mortality with antiviral drugs. antiviral drugs can rich inside the cell.  Problems in developing Antiviral agents (The doctor compared anti-viral with antibiotics to show the difference): Viruses are more diverse than the bacteria, different antigenic proteins which makes it difficult to make drugs. Also, These proteins rapidly undergo replication leading to mutation. The bacteria normally reproduce extra cellularly, whereas viruses reproduce intra-cellularly. Since viruses reproduce intra-cellularly. Drugs are unable to reach intra-cellularly and unable to inhibit the replication process or these processes helps in progression of virus. Antibiotics can affect different types of bacteria. In contrast, antiviral drugs are more specific, with each one typically targeting only a specific virus.  Key is selectivity: Other problems in developing Antiviral agents: Genome diversity can be problematic because each virus has a -Structure of each virus differs -Periodic changes different genome, leading to variations in their antigen protein structures. This means that viruses do not produce the same in the antigenic proteins of the virus (Mutation) antigen proteins and are constantly changing.  Toxicity: The genome of viruses is often very small, which makes it challenging to target them with antiviral drugs. viruses have a high replication rate, which allows them to - Virus is an obligate intracellular parasite, it multiply rapidly and adapt quickly. requires host cell functions for its infection, reproduction, and release (spread). Hence, antiviral agents must be able to inhibit the virus Antiviral drugs need to target the virus without harming the host’s without seriously affecting the host cells. cells. This selective action is necessary to avoid toxicity, or harmful effects, on the patient’s own cells while inhibiting the virus.  Targets for Antiviral agents The structure that will be targeted in the antiviral drug thereby: Structures/ Enzymes important for viral replication: DNA dependent DNA polymerase RNA dependent RNA polymerase RNA dependent DNA polymerase Integrase Protease Neuraminidase  Targets for Antiviral agents 1.Attachment and penetration of the virus into the host cell Viral tropism is the preference or ability of a 1 virus to infect specific types of cells, tissues, or 3 Like HIV will attach to helper T cells. also, They have organs in the body. This depends on factors like The highlighted points are specific surface proteins, which determine their viral tropism, the presence of specific receptors on host cells those that the doctor such as the tropism seen in HIV. that the virus can bind to. focused on during the explanation, but this does not mean that these are the only things that should be 2.Uncoating of virus (e.g., removal of protein 2 memorized. surface and release of the viral (DNA or RNA) 4 The virus will open and will release it’s material. 7 3.Synthesis of new viral components by the host cell as directed by the virus DNA 5 4.Assembly of the components into new virus 6 5.Release of the virus from the host cell.  Targets for Antiviral agents Antiviral drugs targeting each step of the replication: The viral replication: 1- Enfuvirtide affect the receptor so it prevents the HIV virus from binding to host cells. 1- viruses receptor allow them attach to the healthy cells in our body. 2- once the virus attaches there will be confirmational changes 2- Interferon prevent the penetration of the virus to the host cells commonly, used with hepatic-C viral infection. and the virus will penetrate the first cell. 3- the virus is encapsulated by protein coat and some structural 3- Amantadine prevents the uncoating process of the virus, used in the treatment of influenza. units (capsid) and this capsule will open and allow releasing viral nucleic acid once the virus is attached to the cell This 4- Nucleoside reverse transcriptase inhibitors (NRTIs) and Non-nucleoside reverse process called uncoating. transcriptase inhibitors (NNRTIs) they target the nucleic acid syntheses they affect an enzyme called reverse transcriptase, they are commonly used in HIV viral infection. 4- regulatory protein synthesis will synthesize the new viral nucleic acid. 5- Integrase strand transfer inhibitors(INSTIs) also used in treatment of HIV infection they 5- the new viral nucleic acid will be integrated with the host block integrase enzyme which is essential for the integration of viral nucleic acid with the host nucleic acid and will take the over all control of the host cellular genome. machinery to produce the structural and functional proteins 6- protease inhibitors (PIs) used for HIV they inhibit an enzyme called CYP3A which is which are required for the making of new virus. important for synthesis of protein and later assembling packing and releasing viruses. 6- once the proteins are produced, they will be assembled and released to invade other healthy cells. 7- Neuraminidase inhibitors like oseltamivir and zanamivir they will inhibit a viral enzyme called neuraminidase which is essential for releases of new viruses to the circulation. gp120: Binding of the virus to the target cell (the targeted cell in HIV infection is CD4 (TH)cells and HIV Virus structure Dendritic cells) Gp41: Fusion of virus to the cellular membrane Dr also mentioned integrase, which is a protein helps virus to inter the host cell(not labeled in the picture), convert RNA into viral DNA Also, protease enzyme required for virus assembling.  zidovudine is a very important drug. It was the first antiviral Antiretroviral drugs (ART) Antiretroviral drugs: Are drugs used to treat viruses which contains the enzyme Reverse transcriptase drug discovered in 1987. It is one of the most efficacious HIV drugs and is commonly recommended for most HIV patients. Nucleoside reverse transcriptase the Difference between Nucleoside and non-nucleoside is that Nucleoside require inhibitors: Zidovudine activation, they need to be activated by phosphorylation with the help of cellular enzymes in order to work. the drugs will be converted into their active form which is triphosphate Non-Nucleoside reverse transcriptase form, then they can inhibit the enzyme, this is not required in NNRTIS. inhibitors: Nevirapine Protease inhibitors: Indinavir Once proteins are produced, they have to be assembled, this process is going to be targeted by protease inhibitors. Integrase inhibitors: Raltegravir Once the DNA copies are produced, these DNA copies they have to get fused with the host genome with the help of a integrase enzyme. This step can be blocked by this drug. Chemokine receptor antagonist:Maraviroc it is going to inhibit the chemokine receptors and prevent penetration. HIV fusion inhibitor: Enfuvirtide Awhich drug which can inhibit GP120 protein(the protein is important for attachment to the host cell). See the picture in the next slide! HIV virus mechanism 1- gb120 determine the target cell that is CD4 cell 2- once the virus reaches CD4 cell gb41 helps with the fusion or binding of the virus to the cellular wall 3- receptor CXCR5( a chemokine receptor )involved in the conformation change of the virus to the host cell 4- once this communication occurs there will be a full fusion between the cell and the virus 5- once the virus enter the cell uncoating will occur and result in the release of RNA 6- RNA will be converted into viral DNA with the help of Reverse transcription enzyme 7- The viral DNA will integrate with the host genome with the help of integrase enzyme 8- the virus takes the control of the host cellular machinery 9- start producing functional protein for assembling new viruses 10 - the release of new viruses  HAART (Highly active antiretroviral therapy) A combination of drug therapy is called HAART therapy which stands for a highly active antiretroviral therapy (as for the WHO)this combination can effectively suppress the virus.  The standard HIV treatment consists of a combination of at least 3 drugs - 2 NRTIswith either a NNRTI or 1 or 2 PIs(often called “HAART”).  The goals of HAART: -To suppress HIV replication/viral load (< 50 copies/mL) as long as possible. -To reduce the likelihood of the virus developing resistance. -Restore/preserve immunologic function (CD4 count >200 cells/mm3) -To reduce mortality and morbidity rates among HIV-infected people. -To improve their quality of life. -Prevent HIV transmission Like transmission from a pregnant mother to her fetus. Usually patients with HIV die due to opportunistic infection.  When do we start HAART HAART therapy? ART=Anti retroviral therapy As per WHO guidelines: A)Initiate ART if CD4 cell count ≤500 cells/ml. B) As a priority, initiate ART in all individuals with severe/advanced HIV disease (WHO clinical stage 3 or 4) or CD4 count ≤ 350 cells/cu mm C) Initiate ART regardless of WHO clinical stage or CD4 cell count in: Active TB disease HBV co-infection with severe chronic liver disease Pregnant and breastfeeding women with HIV  Herpes Simplex Viruses (HSV) HSV-1: Oral herpes HSV-2: Genital herpes Herpes Simplex Viruses (HSV): Viruses cause a disease called herpes which is one of the most common viral diseases affecting individuals specifically Immune- compromised people, Elders, people with chronic diseases. We have 2 major types of herpes which are herpes simplex 1,2 they differ in the site of the lesions. The difference between them in the next slide.  Herpes simplex 1 Herpes simplex 2 Mainly seen as oral lesion. Oral lesion patients will have: Mainly affects genital region. - rashes, , sores, Itching, fever, and painful Genital lesion patients will have: blisters or ulcers. - Rashes, and blisters. Transmission: Direct contact, close contact, Transmission: Mainly through sexual using infected items, kissing, and saliva. contact. NOTES: - Some patients may not develop any symptoms even though they are carrying the infection. -Sometimes, oral herpes can cause genital herpes, but it usually affects only the oral area.  Antiviral therapy for Herpes viruses It’s Very specific drug, because it is very selective in it’s action, highly effective with the minimal side effects. Acyclovir,Famciclovir: It competes with the Guanosine triphosphate to inhibit DNA polymerase Uses : Herpes simplex and varicella zoster How it work? Acyclovir: Once a person is infected with herpes virus, infected cells they selectively take this Acyclovir drug, and this Acyclovir drug it requires a product, means it requires activation to produce its pharmacological effects it requires an enzyme (thymidine kinase), for conversion of Acyclovir to Acyclovir monophosphate, then to diphosphate, and finally to triphosphate which is the active form of Acyclovir. So where this conversion takes place in? it takes place in the cells which are infected by the virus  Next slide! Anti Influenza drugs Influenza virus consists very important protein like: required for uncoating Neuraminidase inhibitor: (Uses: Influenza A&B)Oseltamivir, Zanamivir Amantadine and Rimantadine: Also, haemagglutin is a protein Inhibits the uncoating & assembly of required for attachment. influenza A virus –Prevents viral replication (Used for only Influenza A)  Treatments for Influenza: Influenza: one of the commonest viral diseases worldwide. It is known as flu. It can produce a lot of symptoms (the most common are): 1. Neuraminidase Inhibitors: - Fever Medications: Oseltamivir, Zanamivir - Running nose Mechanism: Neuraminidase is an enzyme essential for the release of new - Headache viruses into circulation. Inhibiting this enzyme helps control viral - Cough replication and disease transmission in both influenza A and B. - Sneezing - Body weakness 2. M2 Channel Inhibitors: Medications: 1-Amantadine(also, It is a drug commonly used in treatment It is transmitted through: droplets infection during the coughing, sneezing, talking. Mainly, it of the neurologic condition like Parkinson's disease).2-Rimantadine affects the respiratory system Mechanism: These drugs target M2 channels, which are present in influenza type A. By blocking M2 channels, they prevent the uncoating of Immune compromised patients are more likely to get more sever symptoms, also who are the virus after it infects cells, stopping further replication. suffering from chronic diseases, sometimes Influenza can produce fetal symptoms like: Pneumonia -Respiratory distress syndrome (RDS) -Meningitis -Encephalitis -Seizures We have types of influenza: A,B,C,D, these types can also affect animals: a variant of influenza like: H1N1(called swine or bird flu). NOTE: A affects elderly while B affects children. Interferons The name Interferons means(have the ability to interfere with viral replication). Interferons are type of cytokines, which are cell singling molecules in the human system. They are released by the viral infected cells, once a cell is infected, it will release interferons and these interferons will control the replication process. Types: α, β, γ Mechanism of action: Inhibit viral replication by -Preventing the viral penetration -Viral assembly & release -Producing enzymes that inhibit the translation of viral mRNA into viral proteins another important action for interferons: Interferon-alpha 2b: Used in chronic hepatitis B & C Interferons are essential as immunomodulators. They activate specific immune cells, including infections natural killer (NK) cells, B cells, and macrophages. This activation enhances the immune system’s ability Pegylated IFN-α 2a & 2b are superior to conventional IFN to combat viruses and facilitates the elimination of α 2a and 2b. infected cells through apoptosis (programmed cell Pegylated are durgs which are chemically modified interferons. death). Additionally, some types of interferons have (they are more effective than the other types) anti-inflammatory properties, which are particularly useful for managing chronic conditions such as hepatitis B and hepatitis C. 221 notes might be beneficial for this slide: Hepatitis is one of the important viral disease Different type of viruses cause hepatitis: A,B,C,E What is the main target of hepatitis viruses? Liver Most concern are: HBV and HCV because they can transform in chronic state. Once the patients turn into chronic infective stage the liver will inflame (hepatitis), then will be same fibrotic changes or scarring (Cirrhosis), Later It can lead to development of liver cancer. We have to prevent patients from entering chronic stage. By using drugs like interferons which are proteins required for the growth and regulate our immune system. Interferons are produced from: b- lymphocytes , T-lymphocytes, macrophages, fibroblast in response to viral infections. Type of interferons: Alpha, beta, gamma. How can we get them? We can get them from: Mammalian tissues or Through recombinant DNA technology. How they produce potent antiviral activity? Due to inhibition of viral penetration, preventing the viral mRNA, translation of viral proteins, assembly of viral proteins and there release. Interferon –alpha 2b is more commonly used. Recently, there is another type used which is peg interferon –alpha: it is chemically modified interferon with (polyethylene glycol) PEG releated to the (Pegylated) Why this PEG is added? By adding this PEG the duration of infection become prolonged, so the antiviral drug activity will increase. PEG interferon –alpha can be used once weekly and it is more effective than Interferon –alpha 2b, so nowadays PEG interferon –alpha is more used in the treatment of hepatitis C viral infections. It is more effective when administered with Ribavirin (One of the important and commonly used antiviral drug which act by inhibit viral mRNA synthesis. PEG interferon –alpha not harmful. When administered the patients may have flu like symptoms.  Summary Antiviral drugs have revolutionized the treatment and mangement of viral infections, offering improved outcomes and reduced mortality rates. Key Points: oEffectiveness: Antivirals can reduce symptom severity and duration oResistance: Overuse or misuse can lead to viral resistance oSpecificity: Different antivirals target specific viruses oCombination therapy: Antiviral drug combinations can enhance efficacy  team Wishes you the best