Double Arylation of the Indole Side Chain of Tri- and Tetrapodal Tryptophan Derivatives Renders Highly Potent HIV-1 and EV-A71 Entry Inhibitors†.

Olaia Martí-Marí,Rana Abdelnabi,Liang Sun,Sam Noppen,Sofía De La Puente-Secades,Ana San-Félix,Johan Neyts,Dominique Schols,Alberto Mills,Federico Gago,Belén Martínez-Gualda,Ernesto Quesada,María-José Camarasa,Arnaud Boonen

doi:10.1021/acs.jmedchem.1c00315

Olaia Martí-Marí, Rana Abdelnabi + Show 12 more

Open Access

https://doi.org/10.1021/acs.jmedchem.1c00315

Copy DOI

Abstract

We have recently described a new generation of potent human immunodeficiency virus (HIV) and EV-A71 entry inhibitors. The prototypes contain three or four tryptophan (Trp) residues bearing an isophthalic acid moiety at the C2 position of each side-chain indole ring. This work is now extended by both shifting the position of the isophthalic acid to C7 and synthesizing doubly arylated C2/C7 derivatives. The most potent derivative (50% effective concentration (EC50) HIV-1, 6 nM; EC50 EV-A71, 40 nM), 33 (AL-518), is a C2/C7 doubly arylated tetrapodal compound. Its superior anti-HIV potency with respect to the previous C2-arylated prototype is in consonance with its higher affinity for the viral gp120. 33 (AL-518) showed comparable antiviral activities against X4 and R5 HIV-1 strains and seems to interact with the tip and base of the gp120 V3 loop. Taken together, these findings support the interest in 33 (AL-518) as a useful new prototype for anti-HIV/EV71 drug development.

Highlights

The entry of human immunodeficiency virus (HIV) into host cells is a complex multistage process mediated by the viral envelope (Env) spike glycoproteins gp[120] and gp41.1−4 Each of the entry steps is critical in the HIV life cycle and represents an attractive target for the development of new antiviral agents.[5−10] compounds that interfere with these early steps have several advantages over other existing therapeutic approaches that target intracellular viral enzymes such as reverse transcriptase or protease
We have previously reported that a family of tri- and tetrapodal tryptophan (Trp) derivatives inhibits an early step in the infection of HIV by interacting with gp[120] and preventing cell entry.[26]
The new strategy consisted of transferring the carboxylic acid containing aryl moiety from C2 to C7

Summary

Introduction

The entry of human immunodeficiency virus (HIV) into host cells is a complex multistage process mediated by the viral envelope (Env) spike glycoproteins gp[120] and gp41.1−4 Each of the entry steps is critical in the HIV life cycle and represents an attractive target for the development of new antiviral agents.[5−10] compounds that interfere with these early steps have several advantages over other existing therapeutic approaches that target intracellular viral enzymes such as reverse transcriptase or protease. This drug binds directly to gp[120] and avoids the interaction between the virus and cellular CD4 receptors, preventing attachment.[16]

Objectives

Methods

Results

Conclusion