Abstract
Betula alnoides is a medicinal plant in Thai traditional longevity preparations. The crude extracts of this plant possess various biological activities. However, the isolated compounds from this plant have no reports of anti-HIV-1 integrase (IN) activity. Therefore, the present study aims to investigate the anti-HIV-1 integrase and anti-inflammatory effects of isolated compounds from this plant and predict the interaction of compounds with integrase active sites. From the bioassay-guided fractionation of the ethanol extract of B. alnoides stems using chromatographic techniques, five pentacyclic triterpenoid compounds were obtained. They are betulinic acid (1), betulin (2), lupeol (3), oleanolic acid (4), and ursolic acid (5). Compound 2 exhibited the most potent inhibitory activity against HIV-1 IN, with an IC50 value of 17.7 μM. Potential interactions of compounds with IN active sites were investigated using computational docking. The results indicated that active compounds interacted with Asp64, a residue participating in 3′-processing, and Thr66, His67, and Lys159, residues participating in strand-transfer reactions of the integration process. Regarding anti-inflammatory activity, all compounds exerted significant inhibitory effects on LPS-induced nitric oxide production (IC50 < 68.7 μM). Thus, this research provides additional scientific support for the use of B. alnoides in traditional medicine for the treatment of HIV patients.
Highlights
Human immunodeficiency virus (HIV) infection remains a major global public health crisis
Integration of transcribed viral DNA into the host chromosome is mediated by the integrase (IN) enzyme which is a key enzyme for viral integration of the reverse-transcribed viral DNA into the host cell genome, an essential step in the HIV life cycle [4]. e integration requires two catalytic reactions, referred to as 3′-processing and DNA strand transfer [5]. e full-length IN structure consists of three functional domains. e N-terminal domain, residues 1–51, contains a conserved HCCHZn2+-binding motif. e catalytic core domain, residues 52–210, contains the catalytic triad characterized by Asp64, Asp116, and Glu152. e C-terminal domain, residues 220–288, contributes to DNA binding [6]
From bioassayguided fractionation based on anti-HIV-1 IN activity using the multiplate integration assay (MIA) method, the bioactive water and chloroform fractions were purified by chromatographic techniques to afford five known pentacyclic triterpenoid compounds (Figure 1). ey were identified as three lupane-type compounds: betulinic acid, 1 [16, 17]; betulin, 2 [18]; and lupeol, 3 [19], along with one oleanane-type compound, oleanolic acid, 4 [17], and one ursane-type compound, ursolic acid, 5 [20]
Summary
Human immunodeficiency virus (HIV) infection remains a major global public health crisis. E N-terminal domain, residues 1–51, contains a conserved HCCHZn2+-binding motif. E catalytic core domain, residues 52–210, contains the catalytic triad characterized by Asp, Asp116, and Glu152. E C-terminal domain, residues 220–288, contributes to DNA binding [6]. Only three IN inhibitors, Advances in Pharmacological Sciences i.e., raltegravir, elvitegravir, and dolutegravir, have been approved by the FDA [7]. These drugs have limited clinical benefit because long-term treatments may lead to the emergence of drug resistance and side effects [8]. These drugs have limited clinical benefit because long-term treatments may lead to the emergence of drug resistance and side effects [8]. erefore, finding agents from natural products is an alternative approach for novel HIV-1 inhibitors with high selectivity and low toxicity
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