1995: Saquinavir: First HIV Protease Inhibitor (1995)

Despite AZT and subsequent nucleoside reverse transcriptase inhibitors (NRTIs), HIV viral load
suppression with monotherapy or dual NRTI therapy remained incomplete, and resistance emerged
rapidly. A new mechanistic target—HIV protease, essential for cleaving viral polyproteins into
functional structural and enzymatic components—offered a second front.

The HIV protease enzyme, an aspartyl protease, was structurally characterised through X-ray
crystallography in the late 1980s by several academic and industrial groups. Roche, using
structure-based drug design, designed saquinavir—a peptidomimetic compound designed to fit the
enzyme's active site—guided by crystallographic data. This was among the first drugs to reach
clinical approval through a systematic structure-based design programme.

Saquinavir was approved by the FDA on 6 December 1995 via an accelerated pathway, the fastest
drug approval in FDA history at that time. Its approval was rapidly followed by ritonavir and
indinavir in 1996. The availability of three protease inhibitors enabled the combination therapy
strategy that became HAART (highly active antiretroviral therapy): two NRTIs plus one PI.

The results of HAART, pioneered by David Ho and others, were startling. Clinical trial evidence
from 1996 showed that combination therapy could suppress plasma HIV RNA to below the limit of
detection and produce dramatic CD4 cell recovery. AIDS mortality in the United States fell by
over 60% between 1995 and 1998. HIV infection was transformed from a fatal disease to a
manageable chronic condition.

Saquinavir's impact was not just clinical: it was the proof-of-concept demonstration for
structure-based drug design against a viral target, validating the approach for subsequent
antiviral, antibacterial, and oncology drug discovery.