1. What does the transition state of this reaction look like?
Note that a key step in the previous mechanism is the loss of an alkoxy (sugar) moiety from the position (C2) next to the carboxylate group.
This creates a carbocation (Sn1 process), which is sp2 hybridized.
The initial substrate is sp3 hybridized at C2
Thus it was decided to try to synthesize and test compounds which had a double bond to C2, with the prospect of identifying something which bound tighter than the substrate and which could, therefore, function as an effective inhibitor.

2. Chemical evolution of neuraminidase inhibitors
Note that lower Ki values correspond to more active inhibitors
The final product, Relenza (Zanamivir), has a positively charged guanidinium cation (southern end of molecule)
Thus, it is too polar to be absorbed orally and must be administered by inhalation.

4. Further chemical evolution of neuraminidase inhibitors
While the C5 substituent (glycerol side chain) bound to a polar pocket, some of the more recent analogs have shown there is also a hydrophobic pocket, which can bind more hydrophobic C5 side chains, such as the tertiary amide side chain of I.

6. Note that the actual reaction intermediate (lower left) involves a resonance-stabilized carbocation (with oxygen providing electrons to stabilize the C2 carbocation.
Thus it was decided that the double bond of Relenza (Zanamivir) might be in a somewhat incorrect position for optimal binding.
To prepare a stable compound with the double bond in the optimal position, they had to replace the oxygen of the six-membered ring with a carbon (called a carbon isostere).
Note the improvement in activity as the double bond position is altered.

7. Further chemical evolution of neuraminidase inhibitors
Thus a series of compounds was prepared having an appropriately placed C=C and an adjacent hydrophobic group (in this case a substituted ether linkage).
The most active of these (above) has a branched side chain (3-pentyl side chain) on the ether.
Due to the improvement in inhibitory activity, it was possible to remove the highly polar guanidinium side chain and replace it with a slightly less polar amine side chain.

8. Evolution leading to the final product, Tamiflu.
The carboxylic acid of GS 4071 is still too polar.
Thus, they replaced the acid with an ester, which can be hydrolyzed by esterases.
Compounds related to II (above) are currently in clinical trials. These seem to show a further improvement in selectivity against viruses.

9. What is HSV? HSV = Herpes Simplex Virus
HSV-1 is the ‘usual’ cause of cold sores
HSV-2 is the ‘usual’ cause of genital herpes
Both types look the same under the microscope and share about 50% of their DNA.

10. Major members of the herpesvirus group of the family Herpesviridae
Herpes simplex viruses: HSV-1 and HSV-2
Cytomegalovirus (CMV)
Varicella-zoster virus (VZV)
Epstein-Barr virus (EBV)

11. Varicella-zoster virus (VZV)
The Varicella zoster virus (VZV) is one of the eight herpes viruses known to affect humans (and other vertebrates). It commonly causes chickenpox in children and shingles later in life.

12. Shingles

13. Treatment of Varicella Infection
Acyclovir has been shown to reduce fever and skin lesions in patients with varicella and it use is recommended in healthy patients over 18 years of age.
Acyclovir (ZOVIRAX)

14. Cytomegalovirus
Cytomegalovirus (CMV) is a common virus that infects most people during their life. Most people are infected in early childhood (under 3 years of age) or in the teenage years. Usually there are no symptoms of CMV infection. Since most CMV infections are mild and usually do not cause long-term problems, most people don't even know they are infected. However, CMV can cause problems in a developing baby if the mother gets the infection during pregnancy.

15. Cytomegalovirus (CMV)
After a person has a CMV infection, the virus stays in the body but is not active. The virus can reactivate months or years later, which occurs most often when a person's immune system is weakened.

16. Cytomegalovirus (CMV)
Anyone with a weakened immune system is at risk for problems with CMV infection. A weakened immune system can be related to infection with the human immunodeficiency virus (HIV) or medical treatments.  Medical treatments that can weaken the immune system include: chemotherapy, radiation therapy, steroids, and stem cell or organ transplantation. 

17. Cytomegalovirus (CMV)
A few people will have symptoms such as sore throat, fever, headache and fatigue. People who have weakened immune systems may develop severe symptoms, such as pneumonia or infections of the eyes, liver, or intestinal tract. People with HIV infection should be sure to let their doctor know if they are having any painless blurring of their vision, "floaters" in the eye, light flashes, areas of blindness, or shortness of breath.

18. Treatment of CMV Infection
Gangiclovir, a nucleoside analog of acyclovir, inhibits CMV replication and reduces the severity of CMV syndromes, such as retinitis and gastrointestinal disease.
Deoxyguanosine
Acyclovir
Gangiclovir

19. Epstein-Barr Virus (EBV)
EBV is the etiologic agent of infectious mononucleosis
Symptoms include fever, tender lymph nodes, sore throat, mental fatigue
Treatment is usually supportive
Acyclovir can decrease replication of EBV in culture, but has little impact on clinical illness.

20. HSV-1 and HSV-2