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Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket

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Abstract

Covalent inhibitors form covalent adducts with their target, thus permanently inhibiting a physiological process. Peptide fusion inhibitors, such as T20 (Fuzeon, enfuvirtide) and C34, interact with the N-terminal heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein to form an inactive hetero six-helix bundle (6-HB) to prevent HIV-1 infection of host cells. A covalent strategy was applied to peptide fusion inhibitor design by introducing a thioester group into C34-like peptide. The modified peptide maintains the specific interaction with its target N36. After the 6-HB formation, a covalent bond between C- and N-peptides was formed by an inter-helical acyl transfer reaction, as characterized by various biophysical and biochemical methods. The covalent reaction between the reactive C-peptide fusion inhibitor and its N-peptide target is highly selective, and the reaction greatly increases the thermostability of the 6-HB. The modified peptide maintains high potency against HIV-1-mediated cell–cell fusion and infection.

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Acknowledgments

This work was support by the Natural Science Foundation of China Grants (No. 81072581 and No. U0832001) and Key Tech. of National S&T Major Project of Original New Drug Research grant (2012ZX09301-003-001).

Conflict of interest

All the authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian District, Beijing, 100850, China

    Yu Bai, Huifang Xue, Kun Wang, Lifeng Cai & Keliang Liu

  2. Key Laboratory of Structure Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, 110016, China

    Huifang Xue & Maosheng Cheng

  3. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China

    Jiayin Qiu & Shuwen Liu

  4. Beijing National Laboratory for Molecular Sciences, State Key Laboratory of Structural Chemistry for Unstable and Stable Species, College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China

    Shuangyu Bi & Luhua Lai

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  1. Yu Bai
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  2. Huifang Xue
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  3. Kun Wang
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  4. Lifeng Cai
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  5. Jiayin Qiu
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  7. Luhua Lai
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  9. Shuwen Liu
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Correspondence to Shuwen Liu or Keliang Liu.

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Y. Bai, H. Xue contributed equally to this work.

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Bai, Y., Xue, H., Wang, K. et al. Covalent fusion inhibitors targeting HIV-1 gp41 deep pocket. Amino Acids 44, 701–713 (2013). https://doi.org/10.1007/s00726-012-1394-8

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