The Journey of HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic

Abstract

Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity, and low toxicity in antiretroviral combination therapies used to treat HIV. Until now, >50 structurally diverse classes of compounds have been reported as NNRTIs. Among them, six NNRTIs were approved for HIV-1 treatment, namely, nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). In this perspective, we focus on the six NNRTIs and lessons learned from their journey through development to clinical studies. It demonstrates the obligatory need of understanding the physicochemical and biological principles (lead optimization), resistance mutations, synthesis, and clinical requirements for drugs.

Figure 1.

A) The overall architecture of HIV-1 is shown and B) Three-dimensional structure of HIV-1 RT (p66/p51) in complex with nucleic acids is highlighted in different colors. C) A brief timeline of HIV-1 drug development and in particular the drugs identified for RT are highlighted. The two-dimensional (2D) representation of approved NNRTI drugs is depicted.

Figure 2.

(A) Ligand binding pockets of HIV-1 RT are shown with nevirapine (grey) and zidovudine (green) and the key structural domains are highlighted including non- nucleoside inhibitor-binding pocket (NNIBP) (see text for detail). (B) The NNIBP of HIV-1 RT including important secondary structural domains and amino acid residues in the pocket.

Figure 3.

Venn diagram showing the most common clinically significant NNRTI-resistance mutations published for NNRTI approved drugs.

Figure 4.

The key steps and intermediate compounds in the lead optimization process of NVP. The possible sites of CYP450 metabolism are indicated with a yellow sphere.

Figure 5.

(A) Binding mode of NVP (green) with important amino acid residues in the binding pocket of HIV-1 RT (PDB code: 3V81) and (B) schematic representation of ligand pharmacophore models is encircled in red.

Figure 6.

The key steps, techniques and intermediate compounds in the lead optimization process of DLV. The possible sites of CYP450 metabolism are indicated with a yellow sphere.

Figure 7.

(A) The 2D ligand-interaction diagram of RT and DLV (PDB ID: 1KLM). The important amino acids residues in the binding pocket are shown. (B) The 3D representation of DLV indicating the conformational flexibility by specifying the number of rotatable bonds.

Figure 8.

The lead compounds and important compounds synthesized and tested in the process of EFV lead optimization

Figure 10

A) The binding mode of EFV in the binding pocket of HIV-1 RT (PDB ID: 1JKH) with important amino acids in the pocket and B) the 2D ligand-interaction diagram of EFV is shown.

Figure 11.

Key lead optimization process of ETR and RPV

Figure 12.

The 2D protein-ligand interaction diagram for (A) ETR (PDB ID: 3MEC) and (B) RPV (PDB ID: 2ZD1) and the important amino acids in the NNIBP of RT.

Figure 13.

Schematic representation of (A) ETR bound to K103N mutant (PDB ID: 3MED) and (B) RPV bound to K103N/L100I double mutant (PDB ID: 2ZE2) in the NNIBP of RT.

Figure 14.

2D chemical structures of NNRTIs in clinical development.

Figure 15.

Schematic representation doravirine design and lead optimization process.

Figure 16.

Overlay of X-ray crystal conformations and binding mode of NVP (A) and RPV (B) is shown. Important residues are highlighted.

Figure 17.

(A). Inhibition of DAPY series in wild-type and (B) Inhibition of indolylarylsulfone derivatives influenced by the introduction of halogen atom.

Figure 18.

The X-ray crystal structures of HIV-1 RT in complex with fluorine-containing NNRTIs doravirine (PDB ID: 4NCG, IC₅₀ 0.011 μM, colored green); and KRV-2110 (PDB ID: 3LAK, IC₅₀ 0.0034 μM, colored pink)

Scheme 1:

Synthesis of NVP (8) by Merluzzi et al. and Grozinger et al.

Scheme 2:

Synthesis of key building blocks required for NVP (8)

Scheme 3:

Synthesis of NVP (8) proposed by Grozinger et al.

Scheme 4:

Recent synthetic procedure developed for NVP (8)

Scheme 5:

Synthesis of DLV by Romero et al.

Scheme 6:

Modified synthetic procedure of DLV (34)

Scheme 7:

Recent synthetic procedure developed for DLV (34)

Scheme 8:

Synthesis steps of EFV developed by Pierce et al.

Scheme 9:

Advancements in the synthesis of EFV by Chen et al.

Scheme 10:

Initial synthetic procedure for ETR proposed by De Corte et al.^,

Scheme 11:

Modified synthesis of ETR (64) by Joshi et al.

Scheme 12:

Modified synthesis scheme of ETR (64) by Fier et al.

Scheme 13:

Synthetic procedure developed for RPV (84) by Janssen Pharmaceuticals

Scheme 14:

Modified synthetic process of RPV (84)

Scheme 15:

Alternative synthetic procedure developed for RPV (84)

Scheme 16:

Synthesis of RPV (84) by Heck reaction

Scheme 17:

Synthesis of block 83 by Heck reaction