期刊
PHARMACEUTICALS
卷 15, 期 4, 页码 -出版社
MDPI
DOI: 10.3390/ph15040424
关键词
HIV-1; gp41; fusion inhibitor; human serum albumin; long-acting inhibitor
资金
- National Natural Science Foundation of China [92169112, 81971944]
- Program of Shanghai Academic/Technology Research Leader [20XD1420300]
- CAMS Innovation Fund for Medical Sciences [2021-I2M-1-037]
A protein-based, long-acting HIV fusion inhibitor called FLT was designed and constructed, which binds with human serum albumin in a reversible manner to prolong the half-life of the HIV fusion inhibitor T1144. FLT showed high efficiency in inhibiting HIV infection and is considered a promising candidate for a new protein-based anti-HIV drug.
Recently, a series of highly effective peptide- or protein-based HIV fusion inhibitors have been identified. However, due to their short half-life, their clinical application is limited. Therefore, the development of long-acting HIV fusion inhibitors is urgently needed. Here, we designed and constructed a protein-based, long-acting HIV fusion inhibitor, termed FLT (FN3-L35-T1144), consisting of a monobody, FN3, which contains an albumin-binding domain (ABD), a 35-mer linker (L35), and a peptide-based HIV fusion inhibitor, T1144. We found that FLT bound, via its FN3 component, with human serum albumin (HSA) in a reversible manner, thus maintaining the high efficiency of T1144 against infection by both HIV-1 IIIB (X4) and Bal (R5) strains with IC50 of 11.6 nM and 15.3 nM, respectively, and remarkably prolonging the half-life of T1144 (similar to 27 h in SD rats). This approach affords protein-based HIV fusion inhibitors with much longer halflife compared to enfuvirtide, a peptide-based HIV fusion inhibitor approved for use in clinics. Therefore, FLT is a promising candidate as a new protein-based anti-HIV drug with an improved pharmacokinetic profile.
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