Phosphate Derivatives of 3-Carboxyacylbetulin: SynThesis, In Vitro Anti-HIV and Molecular Docking Study.

Krzysztof Marciniec,Elwira Chrobak,Paweł Pęcak,Aleksandra Dąbrowska,Ewa Bębenek,Monika Kadela-Tomanek,Stanisław Boryczka

doi:10.3390/biom10081148

Krzysztof Marciniec, Elwira Chrobak + Show 5 more

Open Access

https://doi.org/10.3390/biom10081148

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Abstract

Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3–5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid–spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3′,3′-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC50 (half maximal inhibitory concentration) equal to 0.02 μM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.

Highlights

Despite significant advances in medicine and continuous work on new pharmacotherapy methods, in addition to common preventive vaccination programs, in the first two decades of the 21st century, the World Health Organization (WHO) recorded many epidemics of viral diseases
Chemical modification of natural substances is an important method used to obtain promising new therapeutic agents. Pentacyclic triterpenes and their semi-synthetic derivatives are a large group of compounds known to demonstrate biological activity, including antitumor, antiviral, antimalarial, antibacterial, anti-inflammatory, and hepatoprotective effects [2]
Antiviral activity of compounds with pentacyclic triterpene structure has been reported in relation to viruses such as HIV, hepatitis virus C (HCV), various types of influenza viruses, severe acute respiratory syndrome (SARS), hepatitis B virus (HBV), herpes viruses (HSV), human enterovirus 71 (EV71), and Epstein–Barr virus (EBV) [3]

Summary

Introduction

Despite significant advances in medicine and continuous work on new pharmacotherapy methods, in addition to common preventive vaccination programs, in the first two decades of the 21st century, the World Health Organization (WHO) recorded many epidemics of viral diseases. Chemical modification of natural substances is an important method used to obtain promising new therapeutic agents. Pentacyclic triterpenes and their semi-synthetic derivatives are a large group of compounds known to demonstrate biological activity, including antitumor, antiviral, antimalarial, antibacterial, anti-inflammatory, and hepatoprotective effects [2]. The first lupane-type triterpenoid to undergo phase IIb clinical trials was 3-O-(3 ,3 -dimethylsuccinyl)betulinic acid, known as bevirimat (BVM). Further studies on this compound were suspended due to resistance emerging among infected patients [4]. Understanding the mechanism of its antiviral activity has opened a new direction in research on inhibitors of virus maturation [5]

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