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2015 ; 10
(4
): e0121099
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English Wikipedia
Screening of the Pan-African natural product library identifies ixoratannin A-2
and boldine as novel HIV-1 inhibitors
#MMPMID25830320
Tietjen I
; Ntie-Kang F
; Mwimanzi P
; Onguéné PA
; Scull MA
; Idowu TO
; Ogundaini AO
; Meva'a LM
; Abegaz BM
; Rice CM
; Andrae-Marobela K
; Brockman MA
; Brumme ZL
; Fedida D
PLoS One
2015[]; 10
(4
): e0121099
PMID25830320
show ga
The continued burden of HIV in resource-limited regions such as parts of
sub-Saharan Africa, combined with adverse effects and potential risks of
resistance to existing antiretroviral therapies, emphasize the need to identify
new HIV inhibitors. Here we performed a virtual screen of molecules from the
pan-African Natural Product Library, the largest collection of medicinal
plant-derived pure compounds on the African continent. We identified eight
molecules with structural similarity to reported interactors of Vpu, an HIV-1
accessory protein with reported ion channel activity. Using in vitro HIV-1
replication assays with a CD4+ T cell line and peripheral blood mononuclear
cells, we confirmed antiviral activity and minimal cytotoxicity for two
compounds, ixoratannin A-2 and boldine. Notably, ixoratannin A-2 retained
inhibitory activity against recombinant HIV-1 strains encoding patient-derived
mutations that confer resistance to protease, non-nucleoside reverse
transcriptase, or integrase inhibitors. Moreover, ixoratannin A-2 was less
effective at inhibiting replication of HIV-1 lacking Vpu, supporting this protein
as a possible direct or indirect target. In contrast, boldine was less effective
against a protease inhibitor-resistant HIV-1 strain. Both ixoratannin A-2 and
boldine also inhibited in vitro replication of hepatitis C virus (HCV). However,
BIT-225, a previously-reported Vpu inhibitor, demonstrated antiviral activity but
also cytotoxicity in HIV-1 and HCV replication assays. Our work identifies pure
compounds derived from African plants with potential novel activities against
viruses that disproportionately afflict resource-limited regions of the world.