Antiviral Agents, chapter 43

Transcription

1 Antiviral Agents, chapter 43 Different living organisms Eucaryotes Mono or polycellular Cell nucleus; DA May have cell wall sexual and / or asexual replication Animals Plants Fungi Protocista: - Protozoea - Algea Procaryotes Bakteriea: Monocellular, no nucleus - DA single strand, cell wall, asex. replic. Virus RA or DA + protein coating (not really a cell) Use other oramisms ribosomes for protein synth

2 Stages of replication DA or RA Protein Coat - Capsid Protein coat - Envelope (glycoproteins - antigens, not all viruses) Many different shapes May attack: Animals Plants Bacteria (ages)

3 Procaryotes and eucaryotes B Replication Leading strand Lagging strand DA DA polymerase X B P X P B X Transcription DA RA polymerase DA (+) stranded RA Translation mra (+) stranded RA Protein

4 Stages of replication - DA virus Attachment, penetration, uncoating, transfer of DA to cell nucleus Viral DA integrated in host DA transcription translation mra translation Viral replication enzymes Replication Synthesis of more viral DA Viral proteins, Capsid etc Integration of viral proteins in host cell membrane Cancer cell Assembly Release: Budding thru membranes (knoppskyting) Lysis ncogenic viruses

5 Stages of replication - RA virus Alternative A: (-) RA virus (-) stranded RA (+) stranded RA = mra More difficult to treath RA virus infect. More mutation - Less repair mech. than with DA Viral RA replicase mra (+) stranded RA Protein Alternative B: (+) RA virus ( Retrovirus) Alternative C: Retrovirus; (+) RA virus (+) stranded RA (+) stranded RA Viral RA replicase (-) stranded RA (-) DA strand Viral RA replicase Retroviral Reverse transcriptase Protein (+) stranded RA incl. mra Further replication as a DA virus

6 Antiviral Drugs Amantadine and analogs euraminidase Inhibitors ucleoside analogs - Antimetabolites ther comp. that interfere with replication Comp. that interfere with translation (protein synth) Interferon / interferon inducers Specific retroviral drugs Reverse transcriptase inhibitors ucleosides (RTIs) on-nucleosides (RTIs) Protease inhibitors 2 Amantadine Effect against influenza A viruses o longer in use. Inhib. penetration of RA virus Inhib. uncoting

7 euraminidase Inhibitors Effect on influenza virus A and B(?) Inhib. neuraminidase (enzyme that breaks bonds between A* in newly A in formed virus and host cell) Prevents release of virus A: emaglutinin, (glycoprotein) important for bonding between influenza virus and host

8 C 2 Glycopeptide euraminidase S 1 C 2 Sialic acid + Glycopeptide C 2 Glycopeptide Lead compound euramidinase Inhib. (not selective for viral A) First selective drug C 2 C 2 2 TS Sialic acid Carbocyclic drug C 2 DAA 2 C 2 Zanamivir Relenza 2 C 2 seltamivir Tamiflu ( Take my flu )

9 Binding of oseltamivir to A 2 2 ydrophobic pocket DAA C 2 Basic centre better binding than DAA 2 C 2 Zanamivir

10 ucleoside analogs - Antimetabolites (C.f. anticancer compounds) 2 Valtrex Valacyclovir Increase GI absorbtion Xanthine oxidase Esterases 2 Acyclovir Aciclovir Zovirax Adenosine deaminase 2 Guanosine 2 6-Deoxyacyclovir Increased solubility 2 2 Guanosine analog Activity: DA erpes viruses (ex. erpes simplex, varicella, cytomegalo, epstein barr)

11 Viral thymidine kinase ormal cellular enzymes 2 Acyclovir 2 P Preference for the viral enzymes 2 P P P Viral DA polymerase ormal DA / RA chain P R Base R= in DA R= in RA DA Chain 2 P o - o Chain elongation

12 Relatet Structures 2 Esterases 2,-acetal 2 Xanthine oxidase Esterases 2 Ac Ac Valgancyclovir Valcyte Gancyclovir Cymevene Peniciclovir More stable Low oral availability Famciclovir Converted to triphosphates Inhibitors of viral DA polymerases Gancyclovir: ot dependent of viral thymine kinase (better effect CMV, EB)

13 Ribavirin Copegus Rebetol 2 Guanosine analog Fosforylated to triphosphate in vivo Inhib. viral RA polymerase, RA / DA synthesis Broad spectrum (RA and DA viruses, some effect on IV) Used against epatitis in., serious side effects 2 Guanosine Thymidine analogs Cytosine analogs Thymidine C 3 X R R = I, X = R = I, X = 2 (less tox) R = Br, X = R = F, X = R = CF 3, X = 2 Cytosine Cytarabine (ARA-C) Cytarabin, Cytosar, 2 Incorp. DA - faulty viral proteins nly cancer ther in.

14 Adenosine analogs 2 Adenosine 2 Vidarabine (Ara-A) ther comp. that interfere with replication Foscarnet Foscavir a Isolated Streptomyces antibioticus First studied as anticancer drug Interfere with DA synth Tox. Rapid metab. adenosine deaminase P a ot orally avail. o in vivo activation required Inhib. DA polymerase eurotox. Also active against IV a Fludarabine Fludara F 2 Antimetabolite cancer ther. ot good substrate for adenosine deaminase Comp. that interfere with translation (protein synth) Methisazone ne of the oldest antiviral comp. known Inhib protein synth R S 2

15 Interferon / interferon inducers Interferon: Rel small glycoproteins formed in virus infected cells (leukocytes, fibroblasts) Binds to surphase of other cells Initiates events leading to inhib. of mra trascrib. and translation ost spesific (not virus spesific) Interferon Inducers Double stranded RA eparin Dextranes ther bioplolymers Tilorone Side effects

16 Retrovirus IV (humans) Animal viruses resulting in cancer / AIDS 15-39%

17 Procaryotes and eucaryotes Replication DA polymerase Leading strand Lagging strand Stages of replication - RA virus Alternative C: Retrovirus; (+) RA virus DA (+) stranded RA (+) stranded RA (-) DA strand Transcription DA RA polymerase DA Retroviral Reverse transcriptase Translation mra (+) stranded RA Further replication as a DA virus B X P B Protein Specific retroviral drugs Reverse transcriptase inhibitors ucleosides (RTIs) P X B X on-nucleosides (RTIs) Protease inhibitors

18 ucleoside Reverse Transcriptase Inhibitors ucleoside analogs without 3 - DA chain termination Pro-drugs - osphorylated by kinases in vivo Zidovudine (AZT) Retrovir Trizivir Kombi prep. 3 Didanosine (ddi) Videx in vivo P P P 2 Stavudine Zerit Zalcitabine (ddc) 2 Abacavir (ABC) Trizivir Kombi prep. 2 Lamividine (3TC) Epivir Trizivir Compivir Kombi prep. S 2 igher bioavail. than ddc

19 on-ucleoside Reverse Transcriptase Inhibitors (RTI) Binds directly to TR evirapin Viramune Efavirenz / Sustiva Stocrin Me F 3 C Cl FDA 1998 Already resistance J Med Chem 2004, 5923 X activity resist strains Wild type RT mutated X=Cl, F

20 Protease Inhibitors The IV-1 protease is an enzyme crucial for the maturation and assembly of infectious viral particles Translation mra (+) stranded RA Protein (from gag ang gag-pol genes) IV proptease (Aspartase) Virus assemply Mature functional proteins

21 X-ray: IV-1 protease - C2 symmetric homodimeric -ot C2-sym. in related human proteases! Science 1990, 249, 527 The two subunits are rotated 180 from each other J. Med. Chem. 1990,33, 2687 Design of C2 sym. comp. as TS(Intermed) analog of e-pro cleavage (Type 1 comp. did not lead to drugs)

22 Bad water sol. and oral bioavail. -X-ray indicate modification of Cbz allowed Good inhib in vitro (both stereoisomers) Increase water sol. Metabolic oxidation M w >500! Somewhat increased bioavail. without -FDA March 1996, now many resistant strains Ritonavir orvir S -Somewhat lower Mw -Thiazol instead of pyridine S -Ritonavir inhib. 3A4 isozyme of CypP450 Used in combi. with other protease inhib. to suppress their metab.

23 Saquinavir Fortovase 2 Indinavir Crixivan Saquinavir (green) bound to IV-1 Protease elfinavir Viracept Amprenavir Agenerase Lopinavir Kaletra S S