5CMU

Artificial HIV fusion inhibitor AP1 fused to the C-terminus of gp41 NHR

Summary for 5CMU

• Entry DOI: 10.2210/pdb5cmu/pdb
• Related: 5CMZ 5CN0
• Descriptor: Envelope glycoprotein,AP1, GLYCEROL (3 entities in total)
• Functional Keywords: enfuvirtide, hiv fusion inhibitor, ap1, gp41, 6-hb, viral protein
• Biological source: Human immunodeficiency virus 1; More
• Total number of polymer chains: 3
• Total formula weight: 26064.87

Authors

Zhu, Y.,Ye, S.,Zhang, R. (deposition date: 2015-07-17, release date: 2015-09-16, Last modification date: 2024-03-20)

Primary citation

Zhu, X.,Zhu, Y.,Ye, S.,Wang, Q.,Xu, W.,Su, S.,Sun, Z.,Yu, F.,Liu, Q.,Wang, C.,Zhang, T.,Zhang, Z.,Zhang, X.,Xu, J.,Du, L.,Liu, K.,Lu, L.,Zhang, R.,Jiang, S.
Improved Pharmacological and Structural Properties of HIV Fusion Inhibitor AP3 over Enfuvirtide: Highlighting Advantages of Artificial Peptide Strategy.
Sci Rep, 5:13028-13028, 2015

PubMed Abstract: Enfuvirtide (T20), is the first HIV fusion inhibitor approved for treatment of HIV/AIDS patients who fail to respond to the current antiretroviral drugs. However, its clinical application is limited because of short half-life, drug resistance and cross-reactivity with the preexisting antibodies in HIV-infected patients. Using an artificial peptide strategy, we designed a peptide with non-native protein sequence, AP3, which exhibited potent antiviral activity against a broad spectrum of HIV-1 strains, including those resistant to T20, and had remarkably longer in vivo half-life than T20. While the preexisting antibodies in HIV-infected patients significantly suppressed T20's antiviral activity, these antibodies neither recognized AP3, nor attenuated its anti-HIV-1 activity. Structurally different from T20, AP3 could fold into single-helix and interact with gp41 NHR. The two residues, Met and Thr, at the N-terminus of AP3 form a hook-like structure to stabilize interaction between AP3 and NHR helices. Therefore, AP3 has potential for further development as a new HIV fusion inhibitor with improved antiviral efficacy, resistance profile and pharmacological properties over enfuvirtide. Meanwhile, this study highlighted the advantages of artificially designed peptides, and confirmed that this strategy could be used in developing artificial peptide-based viral fusion inhibitors against HIV and other enveloped viruses.

PubMed: 26286358
DOI: 10.1038/srep13028

Experimental method

X-RAY DIFFRACTION (2.113 Å)