CoChat
Sign Up
Cited by 33Chemical Synthesis and AnalysisHIV/AIDS drug development and treatmentHIV Research and Treatment

Cyclic peptide inhibitors of HIV-1 capsid-human lysyl-tRNA synthetase interaction

Open access
Dewan, Varun, Liu, Tao, Chen, Kuan-Ming, Qian, Ziqing, Xiao, Yong, Kleiman, Lawrence, Mahasenan, Kiran V., Li, Chenglong +3 more·2012·ACS Chemical Biology
DOI 10.1021/cb200450wPMC PMC3330833
Open this paper in CoChat — free account

Abstract

The human immunodeficiency virus type 1 (HIV-1) capsid protein (CA) plays a critical role in the viral life cycle. The C-terminal domain (CTD) of CA binds to human lysyl-tRNA synthetase (hLysRS), and this interaction facilitates packaging of host cell tRNA(Lys,3), which serves as the primer for reverse transcription. Here, we report the library synthesis, high-throughput screening, and identification of cyclic peptides (CPs) that bind HIV-1 CA. Scrambling or single-residue changes of the selected peptide sequences eliminated binding, suggesting a sequence-specific mode of interaction. Two peptides (CP2 and CP4) subjected to detailed analysis also inhibited hLysRS/CA interaction in vitro. Nuclear magnetic resonance spectroscopy and mutagenesis studies revealed that both CPs bind to a site proximal to helix 4 of the CA-CTD, which is the known site of hLysRS interaction. These results extend the current repertoire of CA-binding molecules to a new class of peptides targeting a novel site with potential for development into novel antiviral agents.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1021/cb200450w

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Cyclic peptides targeting the LysRS-Gag interaction interface inhibit the protein-protein binding in vitro.

    “Cyclic peptides that target the interaction interface have been developed and function to inhibit the protein-protein binding in vitro (56).”

    From Role of host tRNAs and aminoacyl-tRNA synthetases in retroviral replication (2019) · cites this paper as [56]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 48

  1. Rathbun R. C.; Lockhart S. M.; Stephens J. R. (2006) Current HIV treatment guidelines—an overview. Curr. Pharm. Des. 12, 1045–1063. 16515485
  2. Richman D. D. (2001) HIV chemotherapy. Nature 410, 995–1001. 11309630
  3. Vierling P.; Greiner J. (2003) Prodrugs of HIV protease inhibitors. Curr. Pharm. Des. 9, 1755–1770. 12871195
  4. Tamalet C.; Yahi N.; Tourres C.; Colson P.; Quinson A. M.; Poizot-Martin I.; Dhiver C.; Fantini J. (2000) Multidrug resistance genotypes (insertions in the beta3-beta4 finger subdomain and MDR mutations) of HIV-1 reverse transcriptase from extensively treated patients: incidence and association with other resistance mutations. Virology 270, 310–316. 10792990
  5. Adamson C. S.; Freed E. O. (2010) Novel approaches to inhibiting HIV-1 replication. Antiviral Res. 85, 119–141. PMC2815006 19782103
  6. Mascarenhas A. P.; Musier-Forsyth K. (2009) The capsid protein of human immunodeficiency virus: interactions of HIV-1 capsid with host protein factors. FEBS J. 276, 6118–6127. 19825046
  7. Neira J. L. (2009) The capsid protein of human immunodeficiency virus: designing inhibitors of capsid assembly. FEBS J. 276, 6110–6117. 19825045
  8. Kleiman L.; Jones C. P.; Musier-Forsyth K. (2010) Formation of the tRNALys packaging complex in HIV-1. FEBS Lett. 584, 359–365. PMC2820394 19914238
  9. Adamson C. S.; Freed E. O. (2007) Human immunodeficiency virus type 1 assembly, release, and maturation. Adv. Pharmacol. 55, 347–387. 17586320
  10. Ganser-Pornillos B. K.; Yeager M.; Sundquist W. I. (2008) The structural biology of HIV assembly. Curr. Opin. Struct. Biol. 18, 203–217. PMC2819415 18406133
  11. von Schwedler U. K.; Stray K. M.; Garrus J. E.; Sundquist W. I. (2003) Functional surfaces of the human immunodeficiency virus type 1 capsid protein. J. Virol. 77, 5439–5450. PMC153941 12692245
  12. Adamson C. S.; Salzwedel K.; Freed E. O. (2009) Virus maturation as a new HIV-1 therapeutic target. Expert Opin. Ther. Targets 13, 895–908. PMC2737327 19534569
  13. Pornillos O.; Ganser-Pornillos B. K.; Kelly B. N.; Hua Y.; Whitby F. G.; Stout C. D.; Sundquist W. I.; Hill C. P.; Yeager M. (2009) X-ray structures of the hexameric building block of the HIV capsid. Cell 137, 1282–1292. PMC2840706 19523676
  14. Jiang M.; Mak J.; Ladha A.; Cohen E.; Klein M.; Rovinski B.; Kleiman L. (1993) Identification of tRNAs incorporated into wild-type and mutant human immunodeficiency virus type 1. J. Virol. 67, 3246–3253. PMC237665 8497049
  15. Mak J.; Kleiman L. (1997) Primer tRNAs for reverse transcription. J. Virol. 71, 8087–8095. PMC192263 9343157
  16. Javanbakht H.; Halwani R.; Cen S.; Saadatmand J.; Musier-Forsyth K.; Gottlinger H.; Kleiman L. (2003) The interaction between HIV-1 Gag and human lysyl-tRNA synthetase during viral assembly. J. Biol. Chem. 278, 27644–27651. 12756246
  17. Kobbi L.; Octobre G.; Dias J.; Comisso M.; Mirande M. (2011) Association of mitochondrial Lysyl-tRNA synthetase with HIV-1 GagPol involves catalytic domain of the synthetase and transframe and integrase domains of Pol. J. Mol. Biol. 410, 875–886. 21763493
  18. Halwani R.; Cen S.; Javanbakht H.; Saadatmand J.; Kim S.; Shiba K.; Kleiman L. (2004) Cellular distribution of Lysyl-tRNA synthetase and its interaction with Gag during human immunodeficiency virus type 1 assembly. J. Virol. 78, 7553–7564. PMC434110 15220430
  19. Kovaleski B. J.; Kennedy R.; Khorchid A.; Kleiman L.; Matsuo H.; Musier-Forsyth K. (2007) Critical role of helix 4 of HIV-1 capsid C-terminal domain in interactions with human lysyl-tRNA synthetase. J. Biol. Chem. 282, 32274–32279. 17724017
  20. Kovaleski B. J.; Kennedy R.; Hong M. K.; Datta S. A.; Kleiman L.; Rein A.; Musier-Forsyth K. (2006) In vitro characterization of the interaction between HIV-1 Gag and human lysyl-tRNA synthetase. J. Biol. Chem. 281, 19449–19456. 16702215
  21. Guo M.; Shapiro R.; Morris G. M.; Yang X. L.; Schimmel P. (2010) Packaging HIV virion components through dynamic equilibria of a human tRNA synthetase. J. Phys. Chem. B 114, 16273–16279. PMC3042951 21058683
  22. Na Nakorn P.; Treesuwan W.; Choowongkomon K.; Hannongbua S.; Boonyalai N. (2011) In vitro and in silico binding study of the peptide derived from HIV-1 CA-CTD and LysRS as a potential HIV-1 blocking site. J. Theor. Biol. 270, 88–97. 21093454
  23. Tang C.; Loeliger E.; Kinde I.; Kyere S.; Mayo K.; Barklis E.; Sun Y.; Huang M.; Summers M. F. (2003) Antiviral inhibition of the HIV-1 capsid protein. J. Mol. Biol. 327, 1013–1020. 12662926
  24. Li F.; Goila-Gaur R.; Salzwedel K.; Kilgore N. R.; Reddick M.; Matallana C.; Castillo A.; Zoumplis D.; Martin D. E.; Orenstein J. M.; Allaway G. P.; Freed E. O.; Wild C. T. (2003) PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing. Proc. Natl. Acad. Sci. U.S.A. 100, 13555–13560. PMC263852 14573704
  25. Shi J.; Zhou J.; Shah V. B.; Aiken C.; Whitby K. (2011) Small-molecule inhibition of human immunodeficiency virus type 1 infection by virus capsid destabilization. J. Virol. 85, 542–549. PMC3014163 20962083
  26. Sticht J.; Humbert M.; Findlow S.; Bodem J.; Muller B.; Dietrich U.; Werner J.; Krausslich H. G. (2005) A peptide inhibitor of HIV-1 assembly in vitro. Nat. Struct. Mol. Biol. 12, 671–677. 16041387
  27. Zhang H.; Zhao Q.; Bhattacharya S.; Waheed A. A.; Tong X.; Hong A.; Heck S.; Curreli F.; Goger M.; Cowburn D.; Freed E. O.; Debnath A. K. (2008) A cell-penetrating helical peptide as a potential HIV-1 inhibitor. J. Mol. Biol. 378, 565–580. PMC2695608 18374356
  28. Bocanegra R.; Nevot M.; Domenech R.; Lopez I.; Abian O.; Rodriguez-Huete A.; Cavasotto C. N.; Velazquez-Campoy A.; Gomez J.; Martinez M. A.; Neira J. L.; Mateu M. G. (2011) Rationally designed interfacial peptides are efficient in vitro inhibitors of HIV-1 capsid assembly with antiviral activity. PLoS One 6, e23877. PMC3169566 21931621
  29. Hamada Y.; Shioiri T. (2005) Recent progress of the synthetic studies of biologically active marine cyclic peptides and depsipeptides. Chem. Rev. 105, 4441–4482. 16351050
  30. Laupacis A.; Keown P. A.; Ulan R. A.; McKenzie N.; Stiller C. R. (1982) Cyclosporin A: a powerful immunosuppressant. Can.Med. Assoc. J. 126, 1041–1046. PMC1863293 7074504
  31. Sandhu P.; Xu X.; Bondiskey P. J.; Balani S. K.; Morris M. L.; Tang Y. S.; Miller A. R.; Pearson P. G. (2004) Disposition of caspofungin, a novel antifungal agent, in mice, rats, rabbits, and monkeys. Antimicrob. Agents Chemother. 48, 1272–1280. PMC375331 15047529
  32. Kirkpatrick P.; Raja A.; LaBonte J.; Lebbos J. (2003) Daptomycin. Nat. Rev. Drug Discovery 2, 943–944. 14756140
  33. Lalonde M. S.; Lobritz M. A.; Ratcliff A.; Chamanian M.; Athanassiou Z.; Tyagi M.; Wong J.; Robinson J. A.; Karn J.; Varani G.; Arts E. J. (2011) Inhibition of both HIV-1 reverse transcription and gene expression by a cyclic peptide that binds the Tat-transactivating response element (TAR) RNA. PLoS Pathog 7, e1002038. PMC3098202 21625572
  34. Chen X.; Tan P. H.; Zhang Y.; Pei D. (2009) On-bead screening of combinatorial libraries: reduction of nonspecific binding by decreasing surface ligand density. J. Comb. Chem. 11, 604–611. PMC2765537 19397369
  35. Wang X.; Peng L.; Liu R.; Xu B.; Lam K. S. (2005) Applications of topologically segregated bilayer beads in ’one-bead one-compound’ combinatorial libraries. J. Pept. Res. 65, 130–138. 15686543
  36. Newman J. L.; Butcher E. W.; Patel D. T.; Mikhaylenko Y.; Summers M. F. (2004) Flexibility in the P2 domain of the HIV-1 Gag polyprotein. Protein Sci. 13, 2101–2107. PMC2279828 15238640
  37. Ternois F.; Sticht J.; Duquerroy S.; Krausslich H. G.; Rey F. A. (2005) The HIV-1 capsid protein C-terminal domain in complex with a virus assembly inhibitor. Nat. Struct. Mol. Biol. 12, 678–682. 16041386
  38. Liu T.; Joo S. H.; Voorhees J. L.; Brooks C. L.; Pei D. (2009) Synthesis and screening of a cyclic peptide library: discovery of small-molecule ligands against human prolactin receptor. Bioorg. Med. Chem. 17, 1026–1033. PMC2662701 18234500
  39. Wavreille A. S.; Pei D. (2007) A chemical approach to the identification of tensin-binding proteins. ACS Chem. Biol. 2, 109–118. 17256997
  40. Yoo S.; Myszka D. G.; Yeh C.; McMurray M.; Hill C. P.; Sundquist W. I. (1997) Molecular recognition in the HIV-1 capsid/cyclophilin A complex. J. Mol. Biol. 269, 780–795. 9223641
  41. Datta S. A.; Rein A. (2009) Preparation of recombinant HIV-1 gag protein and assembly of virus-like particles in vitro. Methods Mol. Biol. 485, 197–208. PMC6776244 19020827
  42. Joo S. H.; Xiao Q.; Ling Y.; Gopishetty B.; Pei D. (2006) High-throughput sequence determination of cyclic peptide library members by partial Edman degradation/mass spectrometry. J. Am. Chem. Soc. 128, 13000–13009. 17002397
  43. Matsuo H.; Kupce E.; Li H.; Wagner G. (1996) Increased sensitivity in HNCA and HN(CO)CA experiments by selective C beta decoupling. J Magn. Reson. B 113, 91–96. 8888595
  44. Kay L.; Ikura M.; Tschudin R.; Bax A. (1990) Three-dimensional triple-resonance NMR spectroscopy of isotopically enriched proteins. J. Magn. Reson. 89, 18. 22152361
  45. Ikura M.; Kay L. E.; Bax A. (1990) A novel approach for sequential assignment of 1H, 13C, and 15N spectra of proteins: heteronuclear triple-resonance three-dimensional NMR spectroscopy. Application to calmodulin. Biochemistry 29, 4659–4667. 2372549
  46. Wijmenga S. S.; van Mierlo C. P.; Steensma E. (1996) Doubly sensitivity-enhanced 3D TOCSY-HSQC. J. Biomol. NMR 8, 319–330. 20686884
  47. Zhang O.; Kay L. E.; Olivier J. P.; Forman-Kay J. D. (1994) Backbone 1H and 15N resonance assignments of the N-terminal SH3 domain of drk in folded and unfolded states using enhanced-sensitivity pulsed field gradient NMR techniques. J. Biomol. NMR 4, 845–858. 7812156
  48. Delaglio F.; Grzesiek S.; Vuister G. W.; Zhu G.; Pfeifer J.; Bax A. (1995) NMRPipe: a multidimensional spectral processing system based on UNIX pipes. J. Biomol. NMR 6, 277–293. 8520220

Cited by

Sorted by citations

Authors
Dewan, V., Liu, T., Chen, K.-M., Qian, Z., Xiao, Y., Kleiman, L., Mahasenan, K. V., Li, C., Matsuo, H., Pei, D., & Musier-Forsyth, K.
Affiliations
  • The Ohio State University (US)
  • University of Minnesota (US)
  • Jewish General Hospital (CA)
Corresponding author
Pei, Dehua
ORCID
Venue
ACS Chemical Biology
Publisher
American Chemical Society (ACS)
Published
2012-02-13
Volume
7
Issue
4
Pages
761-769
ISSN
  • 1554-8929 (ISSN-L)
  • 1554-8937
DOI
10.1021/cb200450w
PMC
PMC3330833
OpenAlex
W2095491500
Cited by
33
References
4
Citations by year
2025: 1 · 2024: 2 · 2023: 1 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 2 · 2017: 3 · 2016: 1 · 2015: 5 · 2014: 3 · 2013: 9 · 2012: 3
FWCI
2.57
Type
journal article
Language
en
Open access
Licence
Locations
  • ACS Chemical Biology (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
Keywords
HIV-1 capsid protein, cyclic peptides, lysyl-tRNA synthetase, antiviral agents, peptide library synthesis, high-throughput screening, protein-protein interaction inhibition
MeSH terms
Antiviral Agents, Binding Sites, Humans, Lysine-tRNA Ligase, Magnetic Resonance Spectroscopy, Peptides, Cyclic, Protein Binding, HIV-1, Capsid Proteins, Small Molecule Libraries, High-Throughput Screening Assays

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review