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Review
. 2022 Oct 20;58(84):11762-11782.
doi: 10.1039/d2cc04541a.

Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance

Arun K Ghosh  1 , Irene T Weber  2 , Hiroaki Mitsuya  3   4   5
Affiliations
Review

Beyond darunavir: recent development of next generation HIV-1 protease inhibitors to combat drug resistance

Arun K Ghosh et al. Chem Commun (Camb). .

Abstract

We report our recent development of a conceptually new generation of exceptionally potent non-peptidic HIV-1 protease inhibitors that displayed excellent pharmacological and drug-resistance profiles. Our X-ray structural studies of darunavir and other designed inhibitors from our laboratories led us to create a variety of inhibitors incorporating fused ring polycyclic ethers and aromatic heterocycles to promote hydrogen bonding interactions with the backbone atoms of HIV-1 protease as well as van der Waals interactions with residues in the S2 and S2' subsites. We have also incorporated specific functionalities to enhance van der Waals interactions in the S1 and S1' subsites. The combined effects of these structural templates are critical to the inhibitors' exceptional potency and drug-like properties. We highlight here our molecular design strategies to promote backbone hydrogen bonding interactions to combat drug-resistance and specific design of polycyclic ether templates to mimic peptide-like bonds in the HIV-1 protease active site. Our medicinal chemistry and drug development efforts led to the development of new generation inhibitors significantly improved over darunavir and displaying unprecedented antiviral activity against multidrug-resistant HIV-1 variants.

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Conflict of interest statement

Conflicts of interest

There are no conflicts to declare.

Figures

Figure 1.
Figure 1.
Structure and activity of inhibitors 1 and 2 (PDB: 21EN).
Figure 2.
Figure 2.
Design models for PIs to combat drug resistance. Promote robust hydrogen bonds through the P2- and P2′-ligands in both the S2 and S2′-subsites. The hydroxyl group to bind to catalytic aspartates mimicking transition-state, and the P1 and P1′-ligands to fill in the S1 and S1′-subsites.
Figure 3.
Figure 3.
Structure of ginkgolide (3), laulimalide (4), azadirachtin (5), platensimycin (6), and Erlbulin (7) natural products
Figure 4.
Figure 4.
Structure of laulimalide (4, green carbons)-bound to β-tubulin. Hydrogen bonds with THP oxygens are shown with dotted lines.
Figure 5.
Figure 5.
Structure and activity of inhibitors 8 and 9 (PDB: 1HXB).
Figure 6.
Figure 6.
Structure and activity of inhibitors 1 and 10. X-ray structure of 10-bound HIV-1 protease (PDB: 317E).
Figure 7.
Figure 7.
Design and synthesis of polycyclic-ether containing highly potent HIV-1 protease inhibitors.
Figure 8.
Figure 8.
Design of Crown-THF P2 ligand
Figure 9.
Figure 9.
Structure and activity of inhibitor 19–21.
Figure 10.
Figure 10.
Inhibitor 19-bound X-ray structure of HIV-1 protease (PDB code: 5ULT). All hydrogen bonds are indicated by dotted lines.
Figure 11.
Figure 11.
Structure and activity of inhibitor 22–23.
Figure 12.
Figure 12.
Inhibitor 22-bound X-ray structure of HIV-1 protease (PDB code: 5TYR). All hydrogen bonds are indicated by dotted lines.
Figure 13.
Figure 13.
Structure and activity of inhibitors 2 and 24–26.
Figure 14.
Figure 14.
Inhibitor 2 shows high genetic barrier to the development of HIV-1 variants in vitro. Top panel A, against HIVNL4–3; bottom panel B, against a mixture of 11 multi-PI-resistant HIV-1 isolates (HIV11MIX). DOI: https://doi.org/10.7554/eLife.28020.005
Figure 15.
Figure 15.
Inhibitor 2-bound X-ray structure of HIV-1 protease. The major orientation of the inhibitor is shown. The inhibitor carbon atoms are shown in green, water molecules are red spheres, and the hydrogen bonds are indicated by dotted lines (PDB ID: 6BZ2).
Figure 16.
Figure 16.
Side view of the S1 subsite. The protein surface is shown in transparent gray. The van der Waals surface for the fluorinated P1-ligand for inhibitor 2 is shown in orange wire mesh and van der Walls contacts are shown by dotted lines.
Figure 17.
Figure 17.
Design of Umb-THF P2 ligand
Figure 18.
Figure 18.
Structure and activity of inhibitors 46–48.
Figure 19.
Figure 19.
Structure and activity of inhibitors 49–52.
Figure 20A.
Figure 20A.
Inhibitor 52-bound HIV-1 protease X-ray structure is shown (PDB code: 6CDJ). The inhibitor carbon atoms are shown in green and hydrogen bonds are shown by black dotted lines.
Figure 20B.
Figure 20B.
Inhibitor 51-bound HIV-1 protease X-ray structure is shown (PDB code: 6CDL). The inhibitor carbon atoms are shown in cyan and hydrogen bonds are shown by black dotted lines.
Figure 21.
Figure 21.
Structure and activity of inhibitors 60–53.
Figure 22.
Figure 22.
Structure and activity of inhibitors 64 and 65.
Figure 23.
Figure 23.
Structure and activity of inhibitors 66–69.
Figure 24.
Figure 24.
Inhibitor 67-bound HIV-1 protease X-ray structure is shown (PDB code: 6OXV). The inhibitor carbon atoms are shown in cyan and hydrogen bonds are shown by black dotted lines.
Figure 25.
Figure 25.
Structure and activity of inhibitors 70–73.
Figure 26.
Figure 26.
Structure and activity of inhibitors 74–77.
Figure 27.
Figure 27.
Structure and activity of inhibitors 78–81.
Figure 28.
Figure 28.
Structure and activity of inhibitors 82 and 83.
Figure 29.
Figure 29.
Inhibitor 83-bound HIV-1 protease X-ray structure is shown (PDB code: 6B3H). The inhibitor carbon atoms are shown in green and hydrogen bonds are shown by black dotted lines.
Scheme 1.
Scheme 1.
Synthetic strategies for the preparation of inhibitor 2
Scheme 2.
Scheme 2.
Synthesis of Crn-THF ligand 27.
Scheme 3.
Scheme 3.
Synthesis of difluoroazidoepoxide 38.
Scheme 4.
Scheme 4.
Synthesis of protease inhibitor 2.
Scheme 5.
Scheme 5.
Synthesis of optically active ligand alcohol 16.
Scheme 6.
Scheme 6.
Synthesis of inhibitors 51 and 52.
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