Antiviral HIV Drugs PDF

Lecture 70 Antiviral Drugs – For HIV infection Dr. Gouri Nair 1  Content Interferon Life cycle of HIV virus Nucleoside Reverse Transcriptase Inhibitor (NRTIs) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTs) Nucleotide Reverse Trans...

Lecture 70 Antiviral Drugs – For HIV infection Dr. Gouri Nair 1  Content Interferon Life cycle of HIV virus Nucleoside Reverse Transcriptase Inhibitor (NRTIs) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTs) Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) 2  Objectives At the end of this lecture, students will be able to – Describe the life cycle of HIV Describe the mechanism of action, ADR and uses of – Nucleoside Reverse Transcriptase Inhibitor (NRTIs) Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTs) Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) 3 Immunomodulator Modulate immune response against virus Activate immune mechanism to target virus Interferons – enhanced production of cytokines Interferons are a group of signaling proteins produced by host cells in response to the presence of various pathogens, such as viruses, bacteria, or tumor cells. IFNs bind to specific cell surface receptor Affect viral replication 4 Types of Interferon 5 1) Receptor Activation 2) Recruitment of STAT Proteins 3) Phosphorylation of STATs 4) Formation of Transcription Complexes (initiate the transcription of interferon-stimulated genes (ISGs). - Protein kinase R (PKR): - 2',5'-Oligoadenylate synthetase (OAS) - MX proteins - MHC Molecules 6 Interferons Inhibit viral penetration, uncoating, mRNA synthesis Suppression of protein synthesis Inhibits translation of viral mRNA to viral proteins IFNs promote apoptosis IFN-α-2a - chronic HBV infection , AIDS related Kaposi’s sarcoma, Chronic hepatitis, hairy cell leukaemia IFN-α-2b – HCV, malignant melanoma, non hodgkin’s lymphoma 7 Adverse effects of IFNs Fever, weakness, nausea, vomiting, headache, myalgia, flu like symptoms Dose related – Bone marrow depression, rashes, alopecia, hepatic and thyroid dysfunction Higher doses – miscarriage Inhibit Cyt-P450 , decreases clearance of theophylline 8 9 HIV 1 0 Anti HIV drugs Nucleoside Reverse Transcriptase Inhibitor (NRTIs) Zidovudine, Stavudine, Lamivudine, Abacavir, Zalcitabine, Emtricitabine, Didanosine Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) Efavirenz, Nevirapine, Delaviridine, Etravirine Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) Tenofovir 1 1 Anti HIV drugs Protease inhibitors Saquinavir, Indinavir, Nelfinavir, Amprenavir, Fosamprenavir, Ritonavir, Lopinavir, Atazanavir, Tipranavir, Darunavir Entry/Fusion inhibitors Enfuvirtide CCR5 inhibitors – Maraviroc Integrase inhibitors – Raltegravir Newer antiviral drugs – Elvitegravir, Bevirimat, Elvucitabine, Vicriciroc 1 2 NRTIs – General Mechanism of Action Activation into triphosphate metabolites by host cell kinase Triphosphate form competes with viral nucleoside triphosphate for viral RT Hinders to produce complementary DNA from RNA NRTIs lack 3’-OH group or have –N3 in place of 3’ OH Termination of DNA chain elongation 1 3 General therapeutic uses In combination with other drugs to avoid development of resistance HAART – synergistic combination of NRTIs and protease inhibitor Combination – sequential blockade of viral replication 1 4 General toxicity Inhibit cellular as well as mitochondrial DNA polymerase Fatal lactic acidosis, severe hepatomegaly and hepatic steatosis Women, obese and alcoholics are more prone to toxicity Intially no disturbance in immune system Later stage, decline in cell mediated immunity - infection 1 5 Zidovudine Thymidine analogue 3’OH group replaced by azido group Palliative treatment for HIV 1, 2 and HTLV I and II ADR Headache, nausea, vomiting, anorexia, fatigue Insomnia, myopathy, myositis Bone marrow toxicity Anaemia, neutropenia 1 6 Non-Nucleoside Reverse Transcriptase inhibitors (NNTRIs) Do not require activation through phosphorylation Bind directly to catalytic site of viral RT Inactivation of enzyme and inhibition of viral DNA synthesis Resistance may develop due to mutation in RT Cross resistance may develop 1 7  General therapeutic uses and ADRs Active against HIV 1 reverse transcriptase only Use with NRTIs and protease inhibitors – synergistic Sequential block at two different steps required for viral reproduction ADR Skin rashes – Stevens-Johnson syndrome Elevation in the level of liver enzyme 1 8 Nucleotide Reverse Transcriptase Inhibitors (NtRTIs) Tenofovir – tenofovir-disoproxil fumarate Analogue of adenosine 5’ Monophosphate Prodrug hydrolysed in liver to tenofovir Phosphorylated to active tenofovir diphosphate Competitively inhibits HIV- RT enzyme 1 9  Tenofovir Used along with other anti HIV drugs Usually well tolerated Nausea, vomiting, diarrhoes and osteomalacia Hepatomegaly, pancreatitis and lactic acidosis Increases plasma levels of diadenosine leading to toxicity Decreases plasma concentration of atazanavir 2 0 Summary NRTIs gets converted to triphosphate metabolites that competes with viral nucleoside triphosphate for viral RT, hinders to produce complementary DNA from RNA Zidovudine is a thymidine analogue used for Palliative treatment for HIV 1, 2 and HTLV I and II NNRTIs - Bind directly to catalytic site of viral RT and inhibits viral DNA synthesis Tenofovir – inhibits HIV - RT enzyme 2 1