Development of a Raltegravir-based Photoaffinity-Labeled Probe for Human Immunodeficiency Virus-1 Integrase Capture.

Nicolino Pala,Sandro Satta,Francesca Esposito,Mario Sechi,Pankaj Kumar Singh,Enzo Tramontano,Vanna Sanna,Mauro Carcelli,Lisa D Haigh

doi:10.1021/acsmedchemlett.0c00009

Abstract

Photoaffinity labeling (PAL) is one of the upcoming and powerful tools in the field of molecular recognition. It includes the determination of dynamic parameters, such as the identification and localization of the target protein and the site of drug binding. In this study, a photoaffinity-labeled probe for full-length human immunodeficiency virus-1 integrase (HIV-1 IN) capture was designed and synthesized, following the structure of the FDA-approved drug Raltegravir. This photoprobe was found to retain the HIV IN inhibitory potential in comparison with its parent molecule and demonstrates the ability to label the HIV-1 IN protein. Putative photoprobe/inhibitor binding sites near the catalytic site were then identified after protein digestion coupled to mass and molecular modeling analyses.

Highlights

Photoaffinity labeling (PAL) is one of the upcoming and powerful tools in the field of molecular recognition
PAL is based on the ability of some functional groups to form reactive species that are able to create covalent bonds if irradiated with particular wavelengths.[5−9] In PAL, a photophore is incorporated into the structure of a ligand capable of interacting with a particular target
The results indicated that photoprobe 1 was able to inhibit the HIV-1 IN catalytic activity, with an IC50 value of 2.3 ± 0.4 μM, it resulted in being 16 times less potent than HL2 and ∼40 times less effective with respect to RAL (IC50s = 2.3 ± 0.4 μM vs IC50 = 0.058 ± 0.02 for 1 and RAL, respectively)

Summary

Introduction

Photoaffinity labeling (PAL) is one of the upcoming and powerful tools in the field of molecular recognition. We sought to design and synthesize a novel photoaffinity probe (1, Chart 1), structurally related to the drug RAL, that could effectively label the viral full-length HIV1 IN, which could be further used for extensive PAL studies.

Results

Conclusion