text: In the beginning the X-ray crystallography did not have a very good resolution so the initial focus was on substrate derived inhibitors instead of structurally based. The Neu5Ac-derived 2-deoxy-α-D-N-acetylneuraminic acid (2-deoxy- α-Neu5Ac) was the first template used and also the first inhibitor tried in vivo in a mouse model of an  influenza infection. The unsubstituted template showed minor effect. Another template Neu5Ac2en (DANA) was tried under same conditions and showed good in vivo effect. With new crystal structure images of the enzyme and Neu5Ac complex emerging and Neu5Ac2en confirmed as an in vivo inhibitor, the focus was on making structure based DANA derivatives. With better X-ray crystal structure a number of important residues in the active site were identified, specifically C4 hydroxyl group. Better effect was achieved by substituting the C4 hydroxyl group with a more basic group, for example an amino group. Further analysis showed that a larger group could be accommodated in the active site. 4-amino-4-deoxy-Neu5Ac2en and 4-deoxy-4-guanidino-Neu5Ac2en were synthesized and proved to be competitive inhibitors for viral neuraminidase and significantly inhibited both A and B influenza replication in vitro and in vivo.  4-deoxy-4-guanidino-Neu5Ac2en showed not only to be the better inhibitor but also showed considerable lower affinity for other isoforms of neuraminidase. For these reasons 4-deoxy-4-guanidino-Neu5Ac2en was selected as the main drug candidate under the name Zanamivir. High polar nature and rapid excretion contribute to the drugs low bioavailability and rapid elimination.