for all hneu isoenzymes, with a difference from 2 to 10 fold inhibition activity, most effective for hneu3 and hneu4. several reports have tested dana-derivatives as inhibitors for hneu2 and hneu3. most derivatives showed reduced inhibition in vitro. however, n5-azidoacetate-c9-azido derivative of dana showed improved inhibition for hneu2 and hneu3. these studies concluded that the active site in the enzymes could tolerate large modifications at c9 better than at n5. testing of c9 amido derivatives of dana showed hneu1-selective inhibitors. these compounds showed more activity then dana and only minor activity for hneu3 with around 25-fold selectivity for hneu1. these studies show that the glycerol side-chain pocket in the active site can potentially be manipulated in the design of isoenzyme selective inhibitors for hneu. a combination of c4 and c7 modified dana derivatives has been reported with moderate selectivity for hneu2 and hneu3. finally c9-triazole derivatives of dana containing an alkoxy group with a nanomolar activity against hneu4 isoenzyme have been reported. with a 500-fold selectivity for hneu4, this is the highest reported selectivity for a hneu isoenzyme to date. usage there are 2 subgroups of na inhibitors that have been approved by regulatory authorities in the us and europe, zanamivir and oseltamivir. both are for the treatment and prevention of influenza. furthermore, peramivir and laninamivir have been approved by regulatory authorities in some parts of asia. laninamivir laninamivir is approved for the treatment of influenza under the tradename inavir in japan but it is still in clinical trial in the usa. laninamivir is a long acting inhaled drug given as a prodrug (laninamivir octanoate). laninamivir is given as a single dose and remains active for at least 5 days and up to 7 days. oseltamivir oseltamivir can be found under tradenames such as agucort®, antiflu, fluvir, fluhalt, gpo-a-flu™, omiflu, rimivat, virobin, oseltamivir and tamiflu®. oseltamivir is used for patients 1 year and older. it is given as one dose, twice a day for the treatment of influenza. in the prevention of influenza, oseltamivir is given as one dose, once a day for at least 10 days after contacting with an infected person and up to six months (during influenza epidemic). the most common side effects of oseltamivir are headache and nausea (in adults) and vomiting, cough and nasal congestion (in children). peramivir peramivir is approved for the treatment of influenza under the tradenames rapiacta® in japan and peramiflu in south korea. in the us and elsewhere, peramivir is undergoing the late-phase clinical trial. peramivir is used as intravenous and was used in the emergency treatment of 2009 h1n1 in select patients. zanamivir zanamivir can be found under tradenames such as relenza™, verenza and z-flu dpi. zanamivir is used for patients 5 years and older. it is given as one 10 mg dose, twice a day for the treatment of influenza. in the prevention of influenza, zanamivir is given as one 10 mg dose, once a day for 10 days after contacting with an infected person or up the 28 days (during influenza epidemic). the most common side effect of zanamivir is reported to be rash. drug resistance currently, there are two classes of antiviral drugs approved for the treatment and prophylaxis of influenza infections. they are the adamantanes and nais. the adamantanes only work on influenza a so since 2010 who recommended the usage of nais for treatment and prophylaxis of influenza a and b infections. in contrast to adamantanes, nais are less toxic and less prone to promote drug-resistant influenza. moreover, they are effective against all neuraminidase subtypes and all strains of influenza. after the influenza pandemic in 2009, there has been great concern about viral resistance to nais. influenza viruses that have reduced sensitivity to nais often contain mutation that affect the shape of the na catalytic site and therefore reduce the binding ability of the inhibitors. the catalytic site of the na has eight functional residues ( r118, d151, r152, r224, e276, r292, r371, and y406) surrounded by eleven framework residues (e119, r156, w178, s179, d198, i222, e227, h274, e277, n294, and e425). resistance to oseltamivir oseltamivir has a large hydrophobic side chain and the na must undergo rearrangement to form a pocket for drug binding by rotating aminoacid e276 and bond with r224. mutations like h274y, r292k and n294s that affect this forming could reduce the inhibitor's efficiency. resistance to zanamivir resistance to zanamivir has been low for both seasonal and pandemic viruses compare to oseltamivir. molecular structure of zanamivir has a guanidino group, this group interacts with the e119 residue in the active center pocket. resistance to zanamivir can be because of mutations that effect binding affinity between the enzyme and the inhibitor. mutation at the e119 residue has been shown to reduce the inhibitors efficiency in vitro. resistance to peramivir peramivir has a guanidino group similar to zanamivir and a hydrophobic group similar to oseltamivir. mutations that effect the efficiency of oseltamivir and zanamivir can also effect peramivir efficiency. resistances to peramivir have been seen at the mutation of h274y residue in vitro. one of these resistances is associated with cross-resistance to peramivir and oseltamivir. peramivir is approved in japan as rapiacta and also available in south korea as peramiflu. resistance to laninamivir no laninamivir resistance has been reported. however it is a concern that resistance to laninamivir is similar to that of zanamivir because of the similarity in binding properties with the na protein. laninamivir octanoate (cs-8958), which is a prodrug of laninamivir (another inhaled nai with long-acting properties), has also been approved in japan and is commercially available under the name of inavir (daiichi sankyo company ltd.