28 - challenges to antiviral discovery Flashcards
what are the two difficulties in developing antivirals
- each virus is unique
2. most viral proteins act by binding to host proteins
explain how the uniqueness of viruses poses a difficulty in developing antiviral drugs
- Each virus requires different drug
- there are no virus drugs that will work on more than one drug
- logistical problem
explain how the viral proteins binding to host proteins poses a difficulty in developing antiviral drugs
- most work by binding to host proteins
- Proteins tend to bind to each other very tightly (proteins are very large, the area that they are connected by is very large) → hard to separate and get a drug that will interfere
- Utilize large contact surfaces → need a large drug, large drugs are problems
- Need to avoid interfering with normal host cells (want to interfere with host protein interacting with viral proteins) → drug has to look like the interface between the two binded proteins
explain how cell signalling systems use protein binding
- messenger molecule transfers information into the cell by binding to host protein A
- once the messenger molecule is bound to host protein A, host protein A becomes attracted to protein B
- host protein A will change its shape on one side to align with the shape of protein B, allowing them to stick together
- once protein B is connected to host protein A, protein B will change its shape a little bit to allow for a messenger molecule to transmit information
explain how viral proteins operate by binding to host protein
- virus binds to host protein A, causes it to change its shape, allowing it to stick to protein B
- when protein A sticks to protein B, protein B changes its shape, allowing a messenger molecule to come in and transfer information
- virus protein activates protein A when the normal information is not there → how it controls the function of the proteins
what is a regulatory protein
proteins that regulate the function of other proteins in the system (viruses that bind to host proteins are regulatory proteins)
when developing a drug, where do you want it to target?
to make a drug, ideally you want it to target the interface between host protein A and the viral protein
how does protein binding work in a lab
- types of drugs that are created for these viruses usually stick to the interface of the drug that was binding to host protein A
- when the drug is in place, the binding surface cant stick to protein A anymore
- technical problem is that the interface is a large surface and it is hard to produce a drug that large → rare to see it outside the lab
why is protein binding difficult to control with drugs
- large drug works in the lab but doesnt work in human
- violate lipinski rules
describe viral enzymes as drug targets including why it is easy to create them, and the two problems they have
- relatively easy to create a drug that will block an enzyme (most enzymes have small molecule as a substrate, the active site is small = small molecule as a drug)
- problem: Viruses carry very few enzymes (you have a limited number of targets for your drugs)
- problem: Most involve nucleic acid replication (host cells also make nucleic acids with similar substrates, mechanisms, structures, active sites) → if you make a drug that blocks the viral enzyme, it will probably block the host cell too = problems and side effects
how many genes do viruses usually have and how many of them are enzymes
- Most viruses have small genomes
- As few as 10 genes
- On average, one 1 or 2 are enzymes
- Most involve nucleic acids (host selectivity problem)
- very difficult to develop a drug against antiviral target
- Most involve nucleic acids (host selectivity problem)
what are the three main viruses where good antiviral drugs exist
- Hepatitus C (cure)
- drug combination
- remarkable therapy
- the only case where you can cure a virus
- Herpes (treat)
- you can prevent the coldsores, but you cannot cure the herpes
- lifelong
- HIV (manage)
- very good drugs to help manage it
- have been cases of people being cured but those are very rare and specialized
- lifelong
what are the three main problems with antiviral drugs
- selectivity
- diagnosis
- resistance
why is selectivity a problem with antiviral drugs
- Kill virus without killing host
- how does your drug only go after the virus?
why is diagnosis a problem with antiviral drugs
- Drugs specific for each virus
- drugs do not have any “cross pollination”
- Many viruses produce similar symptoms
- More than 200 viruses cause colds
- basically indistinguishable
- Only way to know for sure is biochemical test
- ex: cold vs covid
- takes lots of time
- antivirals are best to use during the first few days of infection = time issue
