Review: Viruses
Virus
Genome
Picorna
RNA
Toga
RNA
Retro
RNA
Orthomyxo RNA
Rhabdo
RNA
Paramyxo RNA
Papova
DNA
Adeno
DNA
Herpes
DNA
Pox DNA ds
Hepatitis B DNA
Polarity
+ss
+ss
+ss
-ss
-ss
-ss
ds
ds
ds
1
ds
Segments
1
1
1+1
6-8
1
1
1
1
1
1
Morphology
Icosahedral
Icosahedral
Icosahedral
Helical
Helical
Helical
Icosahedral
Icosahedral
Icosahedral
Complex
Icosahedral
EnvelopedDiseases
No
Polio, Hepatitis A, Colds
Yes
Encephalitis, Rubella
Yes
AIDS
Yes
Influenza
Yes
Rabies
Yes
Parainfluenza, Mumps, Measles
No
Warts
No
Respiratory Infections
Yes
HS, VZ, Mononucleosis, Cancer
Yes
Smallpox
Yes
Serum Hepatitis
Encephalitis and Meningitis
• Encephalitis is a brain inflammation that causes
sudden fever, vomiting, headache, light sensitivity,
stiff neck and back, drowsiness, and irritability.
Meningitis is an infection that causes inflammation of
the meninges that surround the brain and spinal
cord. Symptoms of meningitis include high fever,
headache, nausea, vomiting, and stiff neck.
Encephalitis and Meningitis
• Encephalitis is an inflammation of the
brain. There are many types of
encephalitis, most of which are caused
by infections. Most often these
infections are caused by viruses.
Encephalitis can also be caused by
diseases that cause inflammation of the
brain.
Encephalitis and Meningitis
• Meningitis is an inflammation of the membranes
(called meninges) that surround the brain and spinal
cord. Meningitis may be caused by many different
viruses and bacteria. It can also be caused by
diseases that can trigger inflammation of tissues of
the body without infection (such as systemic lupus
erythematosus and Behcet's disease).
Antiviral Agents: Influenza
http://microbiology.mtsinai.on.ca/presentations/mazzulli/
mazzulli1.html
Review: Chemotherapeutic Agents to
Treat Viral Infections
• Control of Viruses Since viruses lack
the structures and metabolic processes
that are altered by common antibiotics,
antibiotics are virtually useless in
treating viral infections.To date, only a
few chemotherapeutic agents have
been found to be somewhat effective
against just a few limited viruses.
Antiviral Drugs (general)
• 1. amantadine (Symmetrel): used
prophylactically against influenza A in
high-risk individuals.
• 2. rimantidine (Flumadine): used for
treatment and prophylaxis of influenza
A.
Mechanism of Action of
Amantadine and Rimantadine
• These agents were discovered by random
screening and are now known to interfere
with a viral ion channed called matriz (M2)
protein.
• This causes an inhibition of uncoating of the
virus.
• At high concentrations, they also buffer the
pH of the endosomes and prohibit the acidic
environment needed for Hemaglutanin (HA)
to fuse the viral membrane with that of the
endosome.
•
•
•
•
•
•
Structure and mechanism of the M2 proton channel of influenza A virus
Jason R. Schnell1 & James J. Chou1
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical
School, Boston, Massachusetts 02115, USA
Correspondence to: James J. Chou1 Correspondence and requests for materials should
be addressed to J.J.C. (Email: james_chou@hms.harvard.edu).
Top of page Abstract
The integral membrane protein M2 of influenza virus forms pH-gated proton channels in
the viral lipid envelope1. The low pH of an endosome activates the M2 channel before
haemagglutinin-mediated fusion. Conductance of protons acidifies the viral interior and
thereby facilitates dissociation of the matrix protein from the viral nucleoproteins—a
required process for unpacking of the viral genome2. In addition to its role in release of
viral nucleoproteins, M2 in the trans-Golgi network (TGN) membrane prevents premature
conformational rearrangement of newly synthesized haemagglutinin during transport to
the cell surface by equilibrating the pH of the TGN with that of the host cell cytoplasm3.
Inhibiting the proton conductance of M2 using the anti-viral drug amantadine or
rimantadine inhibits viral replication4, 5, 6, 7. Here we present the structure of the
tetrameric M2 channel in complex with rimantadine, determined by NMR. In the closed
state, four tightly packed transmembrane helices define a narrow channel, in which a
'tryptophan gate' is locked by intermolecular interactions with aspartic acid. A carboxyterminal, amphipathic helix oriented nearly perpendicular to the transmembrane helix
forms an inward-facing base. Lowering the pH destabilizes the transmembrane helical
packing and unlocks the gate, admitting water to conduct protons, whereas the Cterminal base remains intact, preventing dissociation of the tetramer. Rimantadine binds
at four equivalent sites near the gate on the lipid-facing side of the channel and stabilizes
the closed conformation of the pore. Drug-resistance mutations are predicted to counter
the effect of drug binding by either increasing the hydrophilicity of the pore or weakening
helix–helix packing, thus facilitating channel opening.
Nature 451, 591-595 (31 January 2008) | doi:10.1038/nature06531; Received 15 July 2007;
Accepted 3 December 2007
Antiviral Drugs (general)
• 3. zanamivir (Relenza): used to limit
the duration of influenza A and B
infections.
• 4. oseltamivir (Tamiflu): used limit the
duration of influenza infections.
OH
OH
OH
O
COOH
O
O
COOEt
O
N
H
HN
NH
NH2
Zanamivir (Relenza)
NH
NH2
Oseltamivir (Tamiflu)
Two different therapeutic
approaches for treating:
A. A DNA virus (e.g. Herpes)
B. An RNA virus (e.g. Influenza)
Neuramindase is an enzyme which is capable of cleaving
the sialic acid sugar moiety from selected glycoproteins and
glycolipids on the surface of infected cells.
This cleavage promotes the release of progeny virus from infected cells.
The neuraminidase enzyme
•
•
•
•
•
•
Neuraminidase is attached to the viral surface by a single hydrophobic
sequence of 29 amino acids
The enzyme can be easily mutated. There are two main types
corresponding to influenza A and B.
However, the active site is located in a deep pocket and the 18 amino
acids making up the active site itself are constant.
The enzyme is critical to the infective process, particularly including
preventing viral aggregation or binding to hemaglutinin or inactivation
by respiratory mucous. It is essential for proper liberation (shedding) of
the new virus.
Both neuraminidase (NA) and hemaglutanin (HA) act as antigens for flu
vaccines.
However, due to the frequency with which influenza A mutates these
proteins, new flu vaccines are required each year.
Transition state analogs
• An early search for inhibitors of neuraminidase was
unsuccessful.
• Once the crystal structure was available, it was decided to
search for transition state analogs.
• Recall that the active site of the enzyme will bind and stabilize
the transition state more effectively than it will stabilize the
substrate itself, thus resulting in an overall decrease in
activation energy for the chemical transformation.