复旦大学：《医学微生物学 Medical Microbiology（MBBS）》课程讲义_理论课_Lecture17（2）-Antiviral therapy

Antiviral therapy- General Principles NIv JIANER LONG. Rh Lab of Medical Microbiology, Department of Medical Microbiology and Parasitology, Shang Medical College of fudan University 138 Yixueyuan R, Shanghai 200032, PR China Email:longjianer@fudan.edu.cn;Tel:+86-21-54237867

Antiviral therapy - General Principles JIANER LONG, Ph.D. Lab of Medical Microbiology, Department of Medical Microbiology and Parasitology, Shang Medical College of Fudan University, 138 Yixueyuan R., Shanghai 200032, PR China Email: longjianer@fudan.edu.cn; Tel.: +86-21-54237867

Effect of chemical& physical agents on viruses Heat is the most reliable method of virus disinfection Most human pathogenic viruses inactivated by exposure to60°cfor30mns Viruses are stable at low temperatures and are routinely stored at-40to-80° Some viruses are rapidly inactivated by drying, others survive well in a desiccated state UV light inactivates viruses Enveloped viruses(lipid in envelope) are inactivated by organic solvents Phenols, alcohols Qacs active against viruses Most active agents are chlorine, hypochlorites, iodine, aldehydes. ethylene oxide

Antiviral Therapy-important notes 1. Virus replication is dependent to the host cells Antiviral must be selective for viral enzyme or protein, or inhibit virus-Specific process 2. Usually antivirals inhibit replication, dont kill virus Reliance on host immune response for ultimate virus elimination 3. High error rate of viral replication Rapid development of drug resistance Need to suppress virus replication rapidly and efficiently

1. Virus replication is dependent to the host cells Antiviral must be selective for viral enzyme or protein, or inhibit virus-specific process 2. Usually antivirals inhibit replication, don’t kill virus Reliance on host immune response for ultimate virus elimination 3. High error rate of viral replication Rapid development of drug resistance Need to suppress virus replication rapidly and efficiently Antiviral Therapy – important notes

ATTACHMENT Click after each step to view process PENETRATION HOST UNCOATING FUNCTIONS Transcription Translation REPLICATIO VIRAL 八 LIFE ASSEMBLY CYCLE ( MATURATION)、 RELEASE MULTIPLICATION

VIRAL LIFE CYCLE ATTACHMENT PENETRATION HOST FUNCTIONS ASSEMBLY (MATURATION) Transcription REPLICATION RELEASE UNCOATING Translation MULTIPLICATION Click after each step to view process

Potential sites of action for antiviral agents · Site of action attachment to the host cell uncoating of the viral genome nucleic acid synthesis assembly of progeny virions release of virus particles from host cell Drugs inhibit ongoing replication at host cell leve and replication will resume on removal of drug agents are not effective in elimination of non replicating or latent virus

Attachment 1. Using agents which imic the virus attachment protein (VAP)and bind to the No virus Entry cellular receptor Virus Entry At cepto ansbedy Aninon Cytoplasm

Attachment 2. Agents which mimic the receptor and bind to the vap Aeeeplo antit°y ntibody tibodY Roeeeto mimie Virus Entry No virus Entry ML「 Cytoplasm

Attachment Example: Fuzeon-anti-retroviral drug (Inhibition of gp41 mediated infusion) HⅣ F凵zE口n enfuvirtide Fuzeon CD4+ T Cell (enfuvirtide)

Example: Fuzeon – anti-retroviral drug (Inhibition of gp41 mediated infusion) Attachment Fuzeon (enfuvirtide)

HIV 9p41 gp120 gp120 CD4 CXCR4 CXCR4 CD4 gp41 CD4 1. gp120 binds to CD4 molecule 2. gp120 changes shape, peels back and binds to chemokine receptor 3. gp4 1 darts out and pierces cell membrane and anchors Virus 4. Fusion of membranes begins

Penetration/Uncoating Difficult to specifically target these stages of the life cycle as relatively little is known about them Pleconaril -blocks attachment uncoating of picornaviruses(eg rhinovirus) Amantadine rimantidine-? Block cellular membrane ion channels Drug treated cells unable to lower ph of the endosomal compartment- needed to allow influenza virus Ha protein to fuse to the cell membrane