Sifuvirtide, a potent HIV fusion inhibitor peptide.
Enfuvirtide (ENF) is currently the only FDA approved HIV fusion inhibitor in clinical use. Searching for more drugs in this category with higher efficacy and lower toxicity seems to be a logical next step. In line with this objective, a synthetic peptide with 36 amino acid residues, called Sifuvirtide (SFT), was designed based on the crystal structure of gp41. In this study, we show that SFT is a potent anti-HIV agent with relatively low cytotoxicity. SFT was found to inhibit replication of all tested HIV strains. The effective concentrations that inhibited 50% viral replication (EC(50)), as determined in all tested strains, were either comparable or lower than benchmark values derived from well-known anti-HIV drugs like ENF or AZT, while the cytotoxic concentrations causing 50% cell death (CC(50)) were relatively high, rendering it an ideal anti-HIV agent. A GST-pull down assay was performed to confirm that SFT is a fusion inhibitor. Furthermore, the activity of SFT on other targets in the HIV life cycle was also investigated, and all assays showed negative results. To further understand the mechanism of action of HIV peptide inhibitors, resistant variants of HIV-1(IIIB) were derived by serial virus passage in the presence of increasing doses of SFT or ENF. The results showed that there was cross-resistance between SFT and ENF. In conclusion, SFT is an ideal anti-HIV agent with high potency and low cytotoxicity, but may exhibit a certain extent of cross-resistance with ENF.
Wang
Rui-Rui
RR
Key Laboratory of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
Yang
Liu-Meng
LM
Wang
Yun-Hua
YH
Pang
Wei
W
Tam
Siu-Cheung
SC
Tien
Po
P
Zheng
Yong-Tang
YT
D002460:Cell Line; D005982:Glutathione Transferase / Q000737:chemistry; D006678:HIV / Q000187:drug effects* / Q000502:physiology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D010455:Peptides / Q000494:pharmacology* / Q000633:toxicity; D014779:Virus Replication / Q000187:drug effects
D023581:HIV Fusion Inhibitors; D010455:Peptides; C505768:sifuvirtide; D005982:Glutathione Transferase