Discovery of Critical Residues for Viral Entry and Inhibition through Structural Insight of HIV-1 Fusion Inhibitor CP621–652

Chong, Huihui; Xue, Yuan; Qiu, Zonglin; Qin, Bo; Han, Ruiyun; Waltersperger, S.; Wang, Meitian; Cui, Sheng; He, Yuxian

doi:10.1074/jbc.m112.354126

Cited by 44 publications

(65 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given that these two residues are connected to the first pocket-inserting residue Trp-628 and both are highly conserved among all HIV-1 strains, it is conceivable that they play important roles for the function of gp41. Indeed, our mutagenesis studies verified their essential roles for HIV-1 Env-mediated cell fusion and virus entry (25). Prominently, single mutations of the M-T hook residues could completely disrupt the infectivity of virus.…”

Section: Discussionsupporting

confidence: 53%

“…In our previous study (25), we found the M-T hook structure adopted by two N-terminal residues (Met-626 and Thr-627) of the fusion inhibitor CP621-652 in the 6-HB core. Here, we have finely characterized its structure and function by several approaches.…”

Section: Discussionmentioning

confidence: 91%

“…1), including CHR-derived peptides CP621-652 and its mutants (Q621A, I622A, W623A, N624A, N625A, M626A, and T627A), C34, MT-C34, AA-C34, TM-C34, T20, and NHR-derived peptides N36 and N41 were synthesized by a standard solid-phase Fmoc (N-(9-fluorenyl)methoxycarbonyl) method as described previously (25). All peptides were acetylated at the N terminus and amidated at the C terminus.…”

Section: Methodsmentioning

confidence: 99%

“…Nonetheless, the alanine substitution of Trp-623 does not affect the antiviral activity of inhibitor. Given that the conformation of Trp-623 could not be defined due to its flexibility in the CP621-652-based 6-HB (25), it is hard to explain the discordance. But one can speculate that the Trp-623-mediated nonspecific hydrophobic interaction may cause this phenomenon.…”

Section: Qiwnnmentioning

confidence: 99%

“…The peptides containing this motif, CP621-652 and its derivative CP32M, showed potent activity against the wild-type and T20-resistant HIV-1 strains (22)(23)(24). Very recently (25), we determined the high resolution crystal structure of CP621-652 complexed by NHR-derived peptide T21. It was found that the N-terminal 621 QIWN-NMT 627 motif of CP621-652 is highly flexible, but the residues Met-626 and Thr-627 adopt a unique hook-like structure (termed M-T hook), which may stabilize the 6-HB conformation thus conferring the antiviral activity of the inhibitor.…”

mentioning

confidence: 99%

See 4 more Smart Citations

The M-T Hook Structure Is Critical for Design of HIV-1 Fusion Inhibitors

Chong

Xue

Sun

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Background:We recently found that N-terminal residues Met-626 and Thr-627 of HIV-1 fusion inhibitor CP621-652 adopt a unique hook-like structure, termed the M-T hook. Results: The structure and function of the M-T hook have been characterized. Conclusion: The M-T hook is critical for the stability and antiviral activity of HIV-1 fusion inhibitors. Significance: Our data provide important information for designing novel HIV-1 fusion inhibitors.

show abstract

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 91%

Section: Methodsmentioning

confidence: 99%

Section: Qiwnnmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

The M-T Hook Structure Is Critical for Design of HIV-1 Fusion Inhibitors

Chong

Xue

Sun

et al. 2012

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

Systematic Evaluation of Fluorination as Modification for Peptide‐Based Fusion Inhibitors against HIV‐1 Infection

et al. 2021

View full text Add to dashboard Cite

With the emergence of novel viruses, the development of new antivirals is more urgent than ever. A key step in human immunodeficiency virus type 1 (HIV-1) infection is six-helix bundle formation within the envelope protein subunit gp41. Selective disruption of bundle formation by peptides has been shown to be effective; however, these drugs, exemplified by T20, are prone to rapid clearance from the patient. The incorporation of non-natural amino acids is known to improve these pharmacokinetic properties. Here, we evaluate a peptide inhibitor in which a critical Ile residue is replaced by fluorinated analogues. We characterized the influence of the fluorinated analogues on the biophysical properties of the peptide. Furthermore, we show that the fluorinated peptides can block HIV-1 infection of target cells at nanomolar levels. These findings demonstrate that fluorinated amino acids are appropriate tools for the development of novel peptide therapeutics.

show abstract

C Peptides as Entry Inhibitors for Gene Therapy

Egerer

Kiem

Laer

2015

Advances in Experimental Medicine and Biology

View full text Add to dashboard Cite

Peptides derived from the C-terminal heptad repeat 2 region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very potent HIV-1 fusion inhibitors. Antiviral genes encoding either membrane-anchored (ma) or secreted (iSAVE) C peptides have been engineered and allow direct in vivo production of the therapeutic peptides by genetically modified host cells. Membrane-anchored C peptides expressed in the HIV-1 target cells by T-cell or hematopoietic stem cell gene therapy efficiently prevent virus entry into the modified cells. Such gene-protection confers a selective survival advantage and allows accumulation of the genetically modified cells. Membrane-anchored C peptides have been successfully tested in a nonhuman primate model of AIDS and were found to be safe in a phase I clinical trial in AIDS patients transplanted with autologous gene-modified T-cells. Secreted C peptides have the crucial advantage of not only protecting genetically modified cells from HIV-1 infection, but also neighboring cells, thus suppressing virus replication even if only a small fraction of cells is genetically modified. Accordingly, various cell types can be considered as potential in vivo producer cells for iSAVE-based gene therapeutics, which could even be modified by direct in vivo gene delivery in future. In conclusion, C peptide gene therapeutics may provide a strong benefit to AIDS patients and could present an effective alternative to current antiretroviral drug regimens.

show abstract

Discovery of Critical Residues for Viral Entry and Inhibition through Structural Insight of HIV-1 Fusion Inhibitor CP621–652

Cited by 44 publications

References 44 publications

The M-T Hook Structure Is Critical for Design of HIV-1 Fusion Inhibitors

The M-T Hook Structure Is Critical for Design of HIV-1 Fusion Inhibitors

Systematic Evaluation of Fluorination as Modification for Peptide‐Based Fusion Inhibitors against HIV‐1 Infection

C Peptides as Entry Inhibitors for Gene Therapy

Contact Info

Product

Resources

About