Ever since John Kendrew solved the three-dimensional (3D) structure of sperm whale myoglobin in 1957 and Max Perutz that of horse hemoglobin in 1960, molecular structural biology entered the domain of medicine. One of the most remarkable examples of structure-guided drug design effort has been the development of drugs for the treatment of human immunodeficiency virus (HIV) infection.
Saquinavir targets HIV protease
The 3D structure of HIV protease was solved in 1989. Based on its structure-activity relation, the protease was considered to be a good target for drug discovery. It hydrolyzes the Gag and Gag-Pol polyproteins of the virus at different cleavage sites. The cleavage products are the structural proteins (envelope glycoproteins), and the reverse transcriptase (RT), integrase (IN) and protease (PR) enzymes. All are packed into new virion particles.
PR is a homodimer with each of the two subunits containing 99 amino acid residues. Two aspartate residues (Asp25) belonging to the two subunits come together at the dimer interface and form the catalytic site of the enzyme. Saquinavir binds to the protease dimer forming several H-bonds with the catalytic aspartates and surrounding amino acid residues. Binding of the normal substrate to the protease is thus prevented.
Publication of the protease structure led to the development of some successful antivirals. The first to reach the market in 1995, with prompt approval from the Food and Drug Administration (FDA), was saquinavir. It was developed by Roche Pharmaceuticals. Remarkably, the time of six years ‘from bench to bedside’ is still a record for any novel drug.
Biktarvy targets HIV intasome
Saquinavir and other HIV protease inhibitors which followed were not free from problems of efficacy and toxicity. Subsequently, drug resistance mutations brought in additional complexity. Research continued towards formulations and development of newer drugs. These were stipulated to work by different mechanisms and target different steps in the HIV replication process.
Another major class of antiretroviral (anti-HIV) drugs emerged in 2007 with the FDA approval of raltegravir, an integrase inhibitor. Eleven years later, in 2018, the FDA approved biktarvy developed by Gilead Sciences, Inc. Biktarvy contains a novel integrase strand transfer inhibitor (INSTI) bictegravir.
In the cytoplasm of the host cell, the genomic RNA of the virus is reverse transcribed to produce a copy of viral DNA (vDNA). Integration of the vDNA into the host cell chromosome is an absolute requirement for HIV replication cycle. The minimum functional complex (synaptic complex) for integration involves the vDNA and IN. It is a large nucleoprotein assembly, referred to as the intasome. IN catalyzes insertion of the two vDNA ends into the host chromosome.
The intasome is a suitable target for antiretroviral INSTIs. An INSTI binds HIV CSC within a pocket formed by the interface between two IN protomers and vDNA. For binding, two Mg2+ coordinate three electronegative heteroatoms in bictegravir and specific amino acid residues of IN.
National Institute of Allergy and Infectious Diseases (National Institutes of Health, USA) continues to support the development of new antiretroviral drugs and further improved HIV treatment can be expected in the near future.
looks ok so far