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. 2019 Sep 12;62(17):8062-8079.
doi: 10.1021/acs.jmedchem.9b00838. Epub 2019 Aug 21.

HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2' Ligands To Optimize Hydrogen Bonding in the Substrate Envelope

Linah N Rusere  1 , Gordon J Lockbaum  1 , Sook-Kyung Lee  2 , Mina Henes  1 , Klajdi Kosovrasti  1 , Ean Spielvogel  2 , Ellen A Nalivaika  1 , Ronald Swanstrom  2 , Nese Kurt Yilmaz  1 , Celia A Schiffer  1 , Akbar Ali  1
Affiliations

HIV-1 Protease Inhibitors Incorporating Stereochemically Defined P2' Ligands To Optimize Hydrogen Bonding in the Substrate Envelope

Linah N Rusere et al. J Med Chem. .

Abstract

A structure-guided design strategy was used to improve the resistance profile of HIV-1 protease inhibitors by optimizing hydrogen bonding and van der Waals interactions with the protease while staying within the substrate envelope. Stereoisomers of 4-(1-hydroxyethyl)benzene and 4-(1,2-dihydroxyethyl)benzene moieties were explored as P2' ligands providing pairs of diastereoisomers epimeric at P2', which exhibited distinct potency profiles depending on the configuration of the hydroxyl group and size of the P1' group. While compounds with the 4-(1-hydroxyethyl)benzene P2' moiety maintained excellent antiviral potency against a panel of multidrug-resistant HIV-1 strains, analogues with the polar 4-(1,2-dihydroxyethyl)benzene moiety were less potent, and only the (R)-epimer incorporating a larger 2-ethylbutyl P1' group showed improved potency. Crystal structures of protease-inhibitor complexes revealed strong hydrogen bonding interactions of both (R)- and (S)-stereoisomers of the hydroxyethyl group with Asp30'. Notably, the (R)-dihydroxyethyl group was involved in a unique pattern of direct hydrogen bonding interactions with the backbone amides of Asp29' and Asp30'. The SAR data and analysis of crystal structures provide insights for optimizing these promising HIV-1 protease inhibitors.

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Figures

Figure 1.
Figure 1.
Structures of HIV protease inhibitors DRV (1), P2′ 4-(1-hydroxymethyl)benzene analogues (2–4) and designed compounds with stereochemically defined P2′ 4-(1-hydroxyethyl)benzene and (12–17) and 4-(1,2-dihydroxyethyl)benzene (22–27) moieties. The canonical nomenclature for inhibitor moiety position is indicated using DRV.
Figure 2.
Figure 2.
Comparison of binding modes of protease inhibitors with 4-(1-hydroxyethyl)benzene and 4-(1,2-dihydroxyethyl)benzene P2′ moieties in the active site of wild-type HIV-1 protease. The two protease monomers are in cyan (denoted as non-prime) and magenta (denoted as prime). Superposition of protease complexes with DRV (1), parent compounds (2–4), and new analogues (12–17 and 22–27). The inhibitors are shown as sticks and HIV protease dimers are shown as ribbons. (B) Zoomed-in active site of superimposed complexes. The inhibitors bind to wild-type HIV protease in similar conformations except minor variations in the S2′ subsite. (C) Fit of inhibitors within the substrate envelope. The substrate envelope is in blue space filling representation, and the superimposed inhibitors are displayed as sticks. There is minimal protrusion of inhibitors outside the active site. (D) Variations in the binding mode of the inhibitors’ P2¢ moieties.
Figure 3.
Figure 3.
Crystal structures of wild-type HIV-1 protease in complex with inhibitors (A) 16, (B) 17, (C) 26, and (D) 27. Both (R)- and (R)-stereoisomers of the P2′ 4-(1-hydroxyethyl)benzene moiety make direct hydrogen bonding interactions with the backbone NH of Asp30′ in the S2′ subsite (A and B). The (R)-stereoisomer of the P2′ 4-(1,2-dihydroxyethyl)benzene moiety makes hydrogen bonding interactions with backbone NH of Asp29′ and Asp30′ (C). The (S)-stereoisomer of the P2′ 4-(1,2-dihydroxyethyl)benzene moiety makes hydrogen bonding interactions with the backbone NH and side chain carboxylate group of Asp30′ (D).
Figure 4.
Figure 4.
Comparison of binding interactions of representative PIs with modified P2′ moieties in the S2′ subsite of HIV-1 protease. Binding interactions of (A) DRV (PDB 6DGX), (B) parent compound 4 (PDB 6OXQ) with the 4-(hydroxymethyl)benzene P2′ moiety, (C) inhibitor 16 with (S)-4-(1-hydroxyethyl)benzene P2′ moiety, (D) inhibitor 17 with the (R)-configuration of the P2′ moiety, (E) inhibitor 26 with (R)-4-(1,2-dihydroxyethyl)benzene P2′ moiety, and (F) inhibitor 27 with the (S)-configuration of the P2′ moiety.
Figure 5.
Figure 5.
Packing of inhibitors (A) 16, (B) 17, (C) 26, and (D) 27 in the S2′ subsite of HIV-1 protease. The protease residues are colored blue to red for increasing van der Waals (vdW) contact potentials with the inhibitor mapped onto the surface of cocrystal structures. Inhibitors and key residues are shown as sticks.
Scheme 1.
Scheme 1.
Synthesis of protease inhibitors incorporating (S)- and (R)-4-(1-hydroxyethyl)benzene as P2′ ligands Reagents and conditions: (a) RNH2, EtOH, 70 °C, 3 h, 79–91%; (b) Na2CO3, EtOAc, H2O, RT, 18 h, 98–100%; (c) R-CBS-Me, BH3-THF (1 M), THF, 0 °C to RT, 3 h, 57–85%; (d) TFA, CH2Cl2, RT, 1 h; (e) DIEA, CH3CN, RT, 24 h, 73–91%; (f) S-CBS-Me, BH3-THF (1 M), THF, 0 °C to RT, 3 h, 47–87%.
Scheme 2.
Scheme 2.
Synthesis of protease inhibitors incorporating (S)- and (R)-4-(1,2-dihydroxyethyl)benzene as P2′ ligands Reagents and conditions: (a) Na2CO3, EtOAc, H2O, RT, 18 h, 75–94%; (b) AD-mix-β, t-BuOH, H2O, RT, 4 h, 68–87%; (c) TFA, CH2Cl2, RT, 1 h; (d) DIEA, CH3CN, RT, 24 h, 33–79%; (e) AD-mix-α, t-BuOH, H2O, RT, 4 h, 47–86%.
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