Naturally occurring Vpr inhibitors from medicinal plants of Myanmar

Abstract

Human immunodeficiency virus type-1 (HIV-1) is a lentiviral family member that encodes the retroviral Gag, Pol, and Env proteins, along with six additional accessory proteins, Tat, Rev, Vpu, Vif, Nef, and Vpr. The currently approved anti-HIV drugs target the Pol and Env encoded proteins. However, these drugs are only effective in reducing viral replication. Furthermore, the drugs’ toxicities and the emergence of drug-resistant strains have become serious worldwide problems. Resistance eventually arises to all of the approved anti-HIV drugs, including the newly approved drugs that target HIV integrase (IN). Drug resistance likely emerges because of spontaneous mutations that occur during viral replication. Therefore, new drugs that effectively block other viral components must be developed to reduce the rate of resistance and suppress viral replication with little or no long-term toxicity. The accessory proteins may expand treatment options. Viral protein R (Vpr) is one of the promising drug targets among the HIV accessory proteins. However, the search for inhibitors continues in anti-HIV drug discovery. In this review, we summarize the naturally occurring compounds discovered from two Myanmar medicinal plants as well as their structure-activity relationships. A total of 49 secondary metabolites were isolated from Kaempferia pulchra rhizomes and Picrasama javanica bark, and the types of compounds were identified as isopimarane diterpenoids and picrasane quassinoids, respectively. Among the isolates, 7 diterpenoids and 15 quassinoids were found to be Vpr inhibitors lacking detectable toxicity, and their potencies varied according to their respective functionalities.

Recent Advances in Kaempferia Phytochemistry and Biological Activity: A Comprehensive Review

“…A CHCl 3 fraction of K. pulchra exhibits Vpr-inhibitory activity at 25l g mL −1 . In addition, isopimarene type diterpenoids isolated from the rhizomes of the plants, kaempulchraol B ( 43 ), kaempulchraol D (45) , kaempulchraol G ( 46 ), kaempulchraol Q ( 20 ), kaempulchraol T ( 36 ), kaempulchraol U ( 50 ), and W ( 22 ) inhibit the expression of Vpr at concentrations from 1.56 to 6.25 µM [25].…”

“…The isopimaranes reported from the Kaempheria species (Table 1) are characterized with the presence of two double bonds; one is mostly ∆ 15(16) , while the other is between ∆ 8(9) or ∆ 8(14) [4,25,74]. From the rhizomes of K. galanga , 12 usual isopimarenes ( 1–8 , 10 , 11 , 14 , and 17 ) were observed that contained a ∆ 8(14),15 motif in addition to the rarely reported oxygenated seco-isopimarane ( 56 ) [16].…”

Targeting Uracil-DNA Glycosylases for Therapeutic Outcomes Using Insights from Virus Evolution

“…A chemical or peptide, designed to inhibit UNG2 association with Vpr, ought to be detrimental to HIV-1 fitness [100]. It is also noted here, that natural plant extracts acting as general inhibitors of Vpr have been reported [101]. Any general Vpr-inhibiting compounds making it into the clinic would have the potential to compromise HIV-1 viability fairly comprehensively [102].…”

Pyrrolactams from Marine Sponge <i>Stylissa massa</i> Collected from Myanmar and Their Anti-Vpr Activities

“…1,2) In order to find Vpr inhibitors, we have established an assay system where we developed tetracycline regulated TREx-HeLa-Vpr cells and studied the inhibition effect of compounds on Vpr by monitoring the proliferation rate of cells. 3) By using this assay, we identified a number of natural small molecules including isopimarane diterpenoids, 3,4) quassinoids, 5) iridoid and bis-iridoid glucosides, 6) xanthone, 7) and triterpenoid 7) from medicinal plants of Myanmar as potent Vpr inhibitors. 8) Interestingly, as infectious microorganisms evolve and develop resistance to existing pharmaceuticals, marine sponges provide novel leads against bacterial, fungal, and viral diseases, although the availability of more sensitive and different bioassay systems to date will be needed for drug discovery against these diseases.…”