Roger J Pomerantz; David L Horn

Disclosures

Nat Med. 2003;9(7) 

In This Article

1991: Additional NRTIs Ready for Approval by the FDA

Despite the original excitement surrounding zidovudine and the wide release of didanosine in 1991,[9] scientists began to recognize that the effect of monotherapy was brief and limited in activity against HIV-1.[10,11] By 1993, AIDS had become the number one killer of young adults in the US.[12] As the number of people dying from AIDS continued to increase, people became increasingly frustrated with the apparent lack of a therapeutic breakthrough on the horizon.

One therapeutic milestone, reported in 1994, was the successful use of zidovudine during pregnancy to prevent HIV-1 transmission to the neonate. The use of zidovudine as a single agent was documented to decrease neonatal transmission of HIV-1 from 25.5% to 8.3%.[13] The effect was particularly surprising given the modest antiviral effects of zidovudine when used as monotherapy. With greater understanding of the virus, drug discovery targets additional to reverse transcriptase were recognized; these included viral protease, the enzyme responsible for the maturation of viral particles to infectious virions ready to infect new host cells. Core proteins of HIV-1 are produced as part of long polypeptides that are cut into smaller pieces by protease to create functional, mature proteins. Protease inhibitors bind to the active site of the enzyme where protein cleavage occurs (Fig. 3) and new viral particles cannot mature and become infectious.[8,14] Protease inhibitors were synthesized through advanced drug discovery processes.[15,16]

Figure 3.

Protease inhibitors: mechanisms of action. Core proteins of HIV-1 are produced as part of long polypeptides that are cut into smaller pieces by protease to create functional and mature proteins. Protease inhibitors bind to the active site, where protein cleavage occurs. With the inhibition of protease, new viral particles cannot mature and do not become infectious. This figure is modified from.[8]

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