ANTIVIRAL DRUGSRESISTANCY =RESISTANCE VIRUS

HOW ?

GENERAL VIRUSES

INFLUENZA VIRUSES

INFLUENZA VIRUS-A

AVIAN INFLUENZA

H5N1

..THE NEXT MUTANT…

LEVEL OF THINKING STRATEGYFOR ANTIVIRAL DRUGS DEVELOPMENT

Non-Specific

Specific

WHAT MEDICINEWE ARELOOKING FOR ?

RESISTANCE

1

2

3

4

RESISTANCY(VIETNAM)

RESISTANCY(VIETNAM &THAILAND)

VIRUS LIFE CYCLE VIRAL DRUGS TARGET

Difference in:AdsorptionPenetrationUncoating

Difference in:Receptor / TargetDrugs StructurePotency

IMMUNOPATHOLOGY

ANTI-VIRALIMMUNORESPONSES

2

3

1

4

IMMUNOTHERAPY

IMMUNOTHERAPY

ANTI-VIRAL

PREVENTIVE THER

ANTIBODY DRUG

THE PROBLEMS :1. RESISTANCY2. IMPORT

TamifluR Oseltamivir is an ethyl ester prodrug which requires ester hydrolysis to be converted to the active form, oseltamivir carboxylate [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate phosphate. The discovery of oseltamivir was possible through rational drug design utilising available x-ray crystal structures of sialic acid analogues bound to the active site of the influenza virus neuraminidase (Lew 2000). Oseltamivir was developed through modifications to the sialic acid analogue framework (including the addition of a lipophilic side chain) that allow the drug to be used orally (Kim 1998). The structural formula is as follows:

The chemical name of zanamivir is 5-(acetylamino)-4-[(aminoiminomethyl)-amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-en onic acidRelenzaR Zanamivir is an orally inhaled powder currently approved in 19 countries for the treatment of, and in two for the prophylaxis of influenza A and B. Zanamivir is a competitive inhibitor of the neuraminidase glycoprotein, which is essential in the infective cycle of influenza viruses. It closely mimics sialic acid, the natural substrate of the neuraminidase

Chemically, rimantadine hydrochloride is alpha-methyltricyclo-[3.3.1.1/3.7]decane-1-methanamine hydrochloride, with a molecular weight of 215.77 FlumadineR Rimantadine is an M2 ion channel inhibitor which specifically inhibits the replication of influenza A viruses by interfering with the uncoating process of the virus. M2 inhibitors block the ion channel formed by the M2 protein that spans the viral membrane (Hay 1985, Sugrue 1991). The influenza virus enters its host cell by receptor-mediated endocytosis. Thereafter, acidification of the endocytotic vesicles is required for the dissociation of the M1 protein from the ribonucleoprotein complexes. Only then are the ribonucleoprotein particles imported into the nucleus via the nuclear pores. The hydrogen ions needed for acidification pass through the M2 channel. Rimantadine blocks the channel (Bui 1996).

Against this exciting background comes the news of drug resistance. Virally encoded drug resistance has been documented against nearly all compounds with antiviral activity, and the genetic basis of resistance is now known.

Summary points1. Resistance has developed to nearly all specific and

effective antiviral agents 2. Resistance has developed to all drugs against HIV, and

treating hepatitis B with nucleoside analogue monotherapy gives rise to drug resistant variants

3. Resistance develops rapidly when viral replication is not maximally suppressed

4. Drug resistant viruses may be transmitted 5. Assays to measure drug resistance are available in

specialised laboratories

REVERS TRANSCRIPTASE(RNA DNA ) RNA

REVERSETRANSCRIPTASE

REVERSETRANSCRIPTASERESISTANCY

REVERSETRANSCRIPTASE

RESISTANCE

RESISTANCE

RESISTANCE

Panel A shows the amino acid chains of both subunits of the protease. The protease inhibitor (ritonavir) occupies the central substrate-binding domain of the enzyme. The sites of amino acid residues most frequently involved in resistance to protease inhibitors are shown as red beads. The designation of the corresponding residues is written in red for the first subunit of the protease and in blue for the other subunit.

PROTEASE

In Panel B, the substrate-binding cavity contains a protease inhibitor (lopinavir) in the context of either the sensitive protease (green) or the resistant protease (red).

RESISTANCE

PROTEASERESISTANCE

MUTASI RESISTEN

RESISTANCE

STOP

VIRUS MUTATION CHANGE IN DRUGS TARGET : Reverse transcriptase Protease Virus surface protein

SOAL UAS :Apa ……Bagaimana ……

Viral resistance to enfuvirtide usually results from mutations located in a stretch of 10 amino acids within HR1.Interestingly, changes in amino acids in gp41 outside HR1 — and even changes in gp120 — appear to be associated with significant differences in the susceptibility of the virus to enfuvirtide.These mutations or polymorphisms probably explain the remarkably wide range of natural susceptibility to enfuvirtide among HIV-1 strains and could participate in the evolution of acquired resistance to enfuvirtide.

C16H28N2O4TamifluR Oseltamivir :ethyl ester oseltamivir carboxylate [3R,4R,5S]-4-acetamido-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate (phosphate)Exact Mass: 312,20Mol. Wt.: 312,40m/e: 312.20 (100.0%), 313.21 (18.4%), 314.21 (2.5%)C, 61,51; H, 9,03; N, 8,97; O, 20,49

O

O

O

NH

O

NH2

C12H22N4O7RelenzaR Zanamivir is 5-(acetylamino)-4-[(aminoiminomethyl)-amino]-2,6-anhydro-3,4,5-trideoxy-D-glycero-D-galacto-non-2-en onic acidExact Mass: 334,15Mol. Wt.: 334,33m/e: 334.15 (100.0%), 335.15 (15.1%), 336.15 (1.6%)C, 43,11; H, 6,63; N, 16,76; O, 33,50

O

HN

NH2

HN

OH

O

HN

O

HO

OH

OH

C12H21NFlumadineR Rimantadine is alpha-methyltricyclo-[3.3.1.1/3.7]decane-1-methanamine (HCl)Exact Mass: 179,17Mol. Wt.: 179,30m/e: 179.17 (100.0%), 180.17 (13.7%)C, 80,38; H, 11,81; N, 7,81

NH2

TamifluR : Oseltamivir

RelenzaR : Zanamivir FlumadineR : Rimantadine

STRUCTURE ACTIVITY RELATIONSHIP BASEDDRUG SHORTCUT-DISCOVERY :? SYNTHESIS FROM MEDICINAL PLANTS ?

?O

O

O

NH

O

NH2

O

HN

NH2

HN

OH

O

HN

O

HO

OH

OH

NH2