Potent and Selective Activity against Human Immunodeficiency Virus 1 (HIV-1) of Thymelaea hirsuta Extracts

Sanna, Giuseppina; Madeddu, Silvia; Murgia, Giuseppe; Serreli, Gabriele; Begala, Michela; Caboni, Pierluigi; Incani, Alessandra; Franci, Gianluigi; Galdiero, Marilena; Giliberti, Gabriele

Historically, natural products have been the most successful source of inspiration for the development of new drugs. Members of the Thymelaeaceae family have been of interest owing to their excellent medicinal value. Given the successful history of natural product-based drug discovery, extracts from the aerial parts of Thymelaea hirsuta were evaluated for their potential anti-human immunodeficiency virus type 1 (HIV-1) activity. Ethyl acetate extracts from leaves (71B) and branches (72B) of Thymelaea hirsuta showed potent and selective activity against HIV-1 wt (EC(50) = 0.8 µg/mL) at non-cytotoxic concentrations (CC(50) > 100 µg/mL). They proved to be active against HIV-1 variants carrying clinically relevant NNRTI and NRTI mutations at low concentration (0.3–4 µg/mL range) and against the M-tropic strain HIV-1 BaL. The 72B extract, chosen as a lead, was not able to inhibit the RT and protease enzymatic functions. Furthermore, it was not virucidal, since exposure of HIV to high concentration did not affect virus infectivity. The pre-clinical safety profile of this extract showed no adverse effect on the growth of Lactobacilli, and non-toxic concentration of the extract did not influence the Caco-2 epithelial cells monolayer integrity. Additionally, extract 72B prevented syncytia formation at low concentration (0.4 µg/mL). The potent inhibitory effect on the syncytia formation in co-cultures showed that 72B inhibits an early event in the replication cycle of HIV. All of these findings prompt us to carry on new studies on Thymelaea hirsuta extracts.