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Medicinal Chemistry Lectures > Antivirals > Flashcards

Antivirals Flashcards

1
Q

What are the drug agents that inhibit viral attachment penetration and early viral replication?

A
  • ADAMANTYL DRUGS
  • NEURAMINIDASE INHIBITOR DRUGS
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2
Q

For Adamantyl Drugs (derivatives of adamantine);

A) What do they target?

B) What does MOA involve?

C) It is a lysosomotropic agent, what does this mean?

D) Within the acid endosome, the basic primary amino group is ionized to?

E) Why are they known as proton sponges?

F) What does the protonated drug bind to? What does this result in?

G) What do all the above processes result in?

A

A)

  • Target Influenza A strains and inhibits viral RNA penetration into the host cells

B)

  • involves disrupting the bioactivity of VIRAL MEMBRANE PROTEIN M2 –> increase membrane permeability of viral lipid coat
  • During viral endocytosis, M2 operates as a transmembrane proton/H+ channel between viral endosome and virion

C)

  • Can pass through the membrane of a viral endosome

D)

  • Drug is ionised to a PROTONATED 4o ammonium form

E)

  • REDUCE H+ FLOW from the viral endosome into virion

F)

  • Protonated drug also binds to HISTIDINE residues inside the M2 channel thus blocking H+ flow

G)

  • Arrest of H+ transfer
  • Prevents virion uncoating, viral infusion (to the host cell) and the release of viral RNA
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3
Q

For Neuraminidase (NA) inhibitor drugs;

A) What do they function as?

B) What does NA inhibition lead to?

C) Where is NA found?

D) What are TWO viral functions that NA does?

A

A)

  • POTENT COMPETITIVE ENZYME INHIBITORS

B)

  • LEADS TO DISRUPTION OF VIRION RELEASE AND AGGREGATION i.e. HALTS VIRAL INFECTION

C)

  • a surface enzyme found in influenza A and B

D)

  • NA FACILITATES THE RELEASE OF NEWLY-FORMED VIRIONS FROM THE HOST CELL SURFACE
  • NA PREVENTS THE AGGREGATION OF NEWLY FORMED VIRIONS ON THE HOST CELL SURFACE

> NA plays a vital role in the activation of newly formed virions

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4
Q

For Neuraminidase (NA);

A) How does it release virions?

B) How does it prevent virion aggregation?

A

A)

NA CAN BREAK THE CHEMICAL CONNECTIONS BETWEEN THE ATTACHED VIRIONS AND HOST CELL SURFACE

  • Virions bind to host cell ‘sialic acid residues’ via various binding interactions with viral HEMAGGLUTININ (HA)
  • NA catalyzes the breakage of the glycosidic bond that links a sialic acid residue to the host cell surface thus severing the connection between the virion and host cell

B)

NA CAN REMOVE THE TERMINAL SIALIC ACID RESIDUES FROM THE SURFACE OF HOST CELLS

  • Newly formed virions can accumulate on the host cell surface via HA binding to the terminal sialic acid residues
  • Elimination of host terminal sialic acid residues by NA is key to effective virion dispersal (i.e. increase viral infection process)
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5
Q

For the biological role of Neuraminidase;

A) What is NANA

B) What is sialic acid?

C) What does NA catalyse the hydrolysis of?

A

A)

  • PRIMARY SUBSTRATE OF NEURAMINIDASE

B)

  • Sialic acid is a polyfunctional N-acetyl sugar found on host cell receptors covering the respiratory tract cell surfaces

C)

  • NA catalyzes the HYDROLYSIS of the NANA-GLYCOSIDIC BOND to the host cell surface via an ENZYME TRANSITION STATE which is a STABILISED OXONIUM CATION SPECIES
  • Free NANA/sialic acid expelled from NA
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6
Q

For the neuraminidase active site;

A) What role do the 12 amino acid residues do?

B) What do the pocket consist of?

C) Outline the properties of these 5 binding sites

A

A)

  • Amino acid residues line the ‘pocket’ of NA active site and are key to the binding of the sialic acid substrate

B)

  • Pocket consists of FIVE KEY BINDING SITES/AREAS

C)

  • S1 = positively charged (ionic + hydrogen bonding) –> bind to positive areas
  • S2 = negatively charged (salt bridge) –> hydroxy binding pocket
  • S3 + S4 = hydrophobic regions –> acetamido binding pocket
  • S5 = polar region (hydrogen bonding) –> polar region

S 1 and S2 is where binding occurs most of the time

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7
Q

For DANA (neuraminidase inhibitor);

A) What does it represent?

B) What does it resemble?

C) What units found in NANA are preserved in DANA for S1 to 5 binding

D) Why cant it be used clinically?

A

A)

  • represents the 1ST NA INHIBITOR

B)

  • Resembles the NANA substrate BUT the 2-OH group is removed (via dehydration) to give a 2,3-C=C bond

C)

  • 2-CO2H, 4-OH, 5-acetamido and the glycerol units found in NANA

D)

  • Lacks specificity to viral NA hence cannot be used clinically
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8
Q

For Zanamivir (neuraminidase inhibitor);

A) What does it represent

B) What is the difference to it from NANA/DANA

C) What is the 4-guanido group allow? What does this result in?

D) Why does the drug have a very poor/low oral BA?

E) How is it administered?

A

A)

  • represents the 1st NA INHIBITOR DRUG

B)

  • Similar to NANA/DANA BUT minus the 4-OH group which is replaced with a larger N-rich basic GUANIDO group

C)

  • Allows good IONIC binding interactions between the inhibitor and -ve charged Glutamic acid (Glu) residues (with extra CO2 - groups) in S2
  • Guanido unit can form a strong ‘IONIC SALT BRIDGE’
  • improves INHIBITOR BINDING vs DANA
  • increases DRUG POTENCY
  • improves SELECTIVITY – binds to NA in Influenza A/B

D)

  • DUE TO HIGHLY IONISABLE GUANIDINE UNIT AND HIGH POTENTIAL FOR DRUG ZWITTERION FORMATION

E)

  • Administered via INTRANASAL, INHALATION and parenteral routes
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9
Q

For Oseltamivir (neuraminidase inhibitor);

A) What does it represent

B) What ring is introduced? What does this do?

C) What does the PENTYLOXY ETHER 3 group do?

D) What does 5-acetamido group do? (only group retained from NANA btw)

E) What type of prodrug does it represent?

F) What does the ester group do?

G) What does the 5(4)-NH2 group do?

H) What does the altered position for the 1,2 C=C bond mean?

I) What does it retain from NANA substrate?

A

A)

  • represents the 1st ORAL NA INHIBITOR DRUG

B)

  • CYCLOHEXENE ring (carbocyclic) system is introduced that is more STABLE

C)

  • maximizing S4 hydrophobic bonding
  • electron-withdrawing = reduce the electron density at the 1,2 C=C bond
  • also increases drug lipophilicity and oral BA
  • drug is more ‘electronically similar’ to the +ve charged oxonium –> INCREASE DRUG BINDING AFFINITY. OR EWG at this position will also be similar to +ve charged oxonium

D)

  • Hydrophobic binding in S3

E)

  • Ester

F)

  • ESTER GROUP INCREASES THE DRUG ORAL BIOACTIVITY BY INCREASING LIPOPHILICITY AND PREVENTION OF DRUG ZWITTERION FORMATION
  • Leads to better potency vs zanamivir

G)

  • Bind ionically to the GLU residues in the S2 pocket
  • Improves inhibitor binding vs 4-OH in NANA

H)

  • The drug now more closely resembles the oxonium TS than any of the previous inhibitors

I)

  • 5-acetamido group
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10
Q

For Peramivir (neuraminidase inhibitor) –> MOST POTENT NA INHIBITOR DRUG

A) What does it retain from past groups

B) what does it possess?

C) What dosage form is it available in?

A

A)

  • RETAINS 5-ACETAMIDO and certain groups from past drugs i.e. GUANIDO (from Zanamivir) and PENTYL (from Oseltamivir)

B)

  • BUT possesses a smaller CYCLOPENTANE ring system and 2o ALCOHOL group (at C-2 cf. NANA)
  • MORE POTENT than previous drugs (vs Influenza A/B) AND effective against AVIAN FLU VIRUSES (e.g. H1N1, H5N1)

C)

  • Non-oral and only available in I.V. form
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11
Q

What happens when there is a basic group alongside the acidic group in neuraminidase inhibitors?

A

CAUSES LOW ORAL ABSORPTION DUE TO ZWITTERION FORMATION/AMPHOTERIC COMPOUNDS

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12
Q

For agents that interfere with viral nucleic acid replication;

A) What are they comprised of?

B) what is their MOA

C) Why do they require IN VIVO BIOACTIVATION VIA KINASE TRIPHOSPHORYLATION?

A

A)

  • ANTIMETABOLITE DRUGS

B)

  • DISRUPT THE VIRAL DNA/RNA REPLICATION PROCESSES BY INCORPORATION INTO VIRAL DNA
  • MAY ALSO INHIBIT MAJOR ENZYMES INVOLVED IN VIRAL REPLICATION PROCESSES

C)

  • Because most function as prodrugs
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13
Q

What are the two major drug groups of Antiretroviral (anti-hiv) agents?

A

Reverse transcriptase inhibitors

  • NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)
  • NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)

HIV protease inhibitors

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14
Q

For Nucleoside Reverse Transcriptase Inhibitors (NRTIs);

A) What do they function as

B) What do they disrupt

C) What is the bioactivation they require? Why?

A

A)

  • Function as nucleoside based competitive inhibitors

B)

  • Disrupt viral DNA synthesis by incorporation into viral DNA

C)

  • ALL NRTIs REQUIRE TRIPHOSPHORYLATION BIOACTIVATION VIA KINASES i.e. ALL OPERATE AS PRODRUGS
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15
Q

For Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs);

A) do they require bioactivation

A

No

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16
Q

For HIV protease inhibitors;

A) What is HIV protease (HIVp)?

B) What does HIVp function as

C) What key role does HIVp play

A

A)

  • HIV PROTEASE (= HIVp or HIV PR) is an essential viral enzyme which is unique to the HIV (AIDS) virus

B)

  • HIVp functions as an ASPARTIC PROTEASE and its primary rôle involves the ‘post-translational’ modification of core proteins (peptide-based substrates) into structural proteins

C)

  • HIVp plays key roles in ALL stages of the HIV lifecycle and represents an important drug target in HIV drug research
17
Q

For HIV PI drugs;

A) What are they sub-classified as?

B) What’s wrong with them 1st generation drugs?

C) What are they designed to target

D) What do they function as?

E) What do they hydrogen bond to?

F) How does binding occur?

G) It is non-scissile, what does this mean? (in relation to F)

A

A)

  • 1st GENERATION’ PEPTIDOMIMETIC PIs
  • 2nd/3rd GENERATION’ NON-PEPTIDE PIs

B)

  • peptidomimetic PIs are hampered by similar issues to many peptide-based drugs i.e. they are UNSTABLE

C)

  • designed to specifically target the HIVp of HIV-1

D)

  • function as TRANSITION-STATE MIMICS of the POLYPEPTIDE SUBSTRATES OF HIVp

E)

  • PIs are capable of HYDROGEN BONDING to TWO important ‘catalytic’ ASPARTATE residues within the HIVp active site
  • These 2 Aspartate (Asp-25) residues AND an ENZYME-BOUND WATER MOLECULE are key to HIVp bioactivity

F)

  • Binding occurs between the CO2 - groups of the aspartate residues and a HYDROXYETHYL unit common to all PIs

G)

  • This unit is NON-SCISSILE –> doesn’t hydrolyze

Medicinal Chemistry Lectures (9 decks)

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