Flavonoids and Acid-Hydrolysis derivatives of Neo-Clerodane diterpenes from Teucrium flavum subsp. glaucum as inhibitors of the HIV-1 reverse transcriptase-associated RNase H function

Benedetta Fois; Angela Corona; Enzo Tramontano; Simona Distinto; Elias Maccioni; Rita Meleddu; Pierluigi Caboni; Costantino Floris; Filippo Cottiglia

doi:10.1080/14756366.2021.1887170

Flavonoids and Acid-Hydrolysis derivatives of Neo-Clerodane diterpenes from Teucrium flavum subsp. glaucum as inhibitors of the HIV-1 reverse transcriptase-associated RNase H function

J Enzyme Inhib Med Chem. 2021 Dec;36(1):749-757. doi: 10.1080/14756366.2021.1887170.

Authors

Benedetta Fois¹, Angela Corona¹, Enzo Tramontano^{1

2}, Simona Distinto¹, Elias Maccioni¹, Rita Meleddu¹, Pierluigi Caboni¹, Costantino Floris³, Filippo Cottiglia¹

Affiliations

¹ Department of Life and Environmental Sciences, University of Cagliari, Cittadella Universitaria di Monserrato, Monserrato, Italy.
² Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Monserrato, Italy.
³ Department of Chemical and Geological Sciences, University of Cagliari, Monserrato, Italy.

Abstract

Bioassay-guided fractionation of the ethyl acetate extract from Teucrium flavum subsp. glaucum, endowed with inhibitory activity towards the HIV-1 reverse transcriptase-associated RNase H function, led to the isolation of salvigenin (1), cirsimaritin (2) and cirsiliol (3) along with the neo-clerodanes teuflavin (4) and teuflavoside (5). Acid hydrolysis of the inactive teuflavoside provided three undescribed neo-clerodanes, flavuglaucins A-C (7-9) and one known neo-clerodane (10). Among all neo-clerodanes, flavuglaucin B showed the highest inhibitory activity towards RNase H function with a IC₅₀ value of 9.1 μM. Molecular modelling and site-directed mutagenesis analysis suggested that flavuglaucin B binds into an allosteric pocket close to RNase H catalytic site. This is the first report of clerodane diterpenoids endowed with anti-reverse transcriptase activity. Neo-clerodanes represent a valid scaffold for the development of a new class of HIV-1 RNase H inhibitors.

Keywords: HIV; RNase H; Teucrium flavum; flavonoids; neo-clerodane diterpenes; reverse transcriptase.

MeSH terms

Diterpenes, Clerodane / chemistry
Diterpenes, Clerodane / isolation & purification
Diterpenes, Clerodane / pharmacology*
Dose-Response Relationship, Drug
Flavonoids / chemistry
Flavonoids / isolation & purification
Flavonoids / pharmacology*
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / genetics
HIV Reverse Transcriptase / metabolism
Hydrogen-Ion Concentration
Hydrolysis
Models, Molecular
Molecular Conformation
Mutagenesis, Site-Directed
Plant Extracts / chemistry
Plant Extracts / isolation & purification
Plant Extracts / pharmacology*
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / isolation & purification
Reverse Transcriptase Inhibitors / pharmacology*
Ribonuclease H / antagonists & inhibitors*
Ribonuclease H / genetics
Ribonuclease H / metabolism
Structure-Activity Relationship
Teucrium / chemistry*

Substances

Diterpenes, Clerodane
Flavonoids
Plant Extracts
Reverse Transcriptase Inhibitors
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase
Ribonuclease H