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Rationally Designed Peptides as Efficient Inhibitors of Nucleic Acid Chaperone Activity of HIV-1 Nucleocapsid Protein
- Source :
- Biochemistry, Biochemistry, American Chemical Society, 2018, 57 (30), pp.4562-4573. ⟨10.1021/acs.biochem.8b00527⟩, Biochemistry, 2018, 57 (30), pp.4562-4573. ⟨10.1021/acs.biochem.8b00527⟩
- Publication Year :
- 2018
- Publisher :
- HAL CCSD, 2018.
-
Abstract
- Due to its essential roles in the viral replication cycle and to its highly conserved sequence, the nucleocapsid protein (NCp7) of the human immunodeficiency virus type 1 is a target of choice for inhibiting replication of the virus. Most NCp7 inhibitors identified so far are small molecules. A small number of short peptides also act as NCp7 inhibitors by competing with its nucleic acid (NA) binding and chaperone activities but exhibit antiviral activity only at relatively high concentrations. In this work, in order to obtain more potent NCp7 competitors, we designed a library of longer peptides (10-17 amino acids) whose sequences include most of the NCp7 structural determinants responsible for its specific NA binding and destabilizing activities. Using an in vitro assay, the most active peptide (pE) was found to inhibit the NCp7 destabilizing activity, with a 50% inhibitory concentration in the nanomolar range, by competing with NCp7 for binding to its NA substrates. Formulated with a cell-penetrating peptide (CPP), pE was found to accumulate into HeLa cells, with low cytotoxicity. However, either formulated with a CPP or overexpressed in cells, pE did not show any antiviral activity. In vitro competition experiments revealed that its poor antiviral activity may be partly due to its sequestration by cellular RNAs. The selected peptide pE therefore appears to be a useful tool for investigating NCp7 properties and functions in vitro, but further work will be needed to design pE-derived peptides with antiviral activity.
- Subjects :
- Models, Molecular
0301 basic medicine
Anti-HIV Agents
Drug Evaluation, Preclinical
HIV Infections
Peptide
gag Gene Products, Human Immunodeficiency Virus
Biochemistry
Conserved sequence
03 medical and health sciences
Nucleic Acids
Humans
[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology
Amino Acid Sequence
ComputingMilieux_MISCELLANEOUS
chemistry.chemical_classification
030102 biochemistry & molecular biology
biology
Small molecule
In vitro
3. Good health
Amino acid
030104 developmental biology
chemistry
Viral replication
Drug Design
Chaperone (protein)
HIV-1
Nucleic acid
biology.protein
Peptides
HeLa Cells
Subjects
Details
- Language :
- English
- ISSN :
- 00062960 and 15204995
- Database :
- OpenAIRE
- Journal :
- Biochemistry, Biochemistry, American Chemical Society, 2018, 57 (30), pp.4562-4573. ⟨10.1021/acs.biochem.8b00527⟩, Biochemistry, 2018, 57 (30), pp.4562-4573. ⟨10.1021/acs.biochem.8b00527⟩
- Accession number :
- edsair.doi.dedup.....35d31a8b514515dbba61049b1f3cc696