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HIV-1 PR aptamer
Description
In 2015, Duclair S, Gautam A, Ellington A, et al. selexed several RNA aptamers targeting the human immunodeficiency virus type 1 (HIV-1) protease (PR) using a method called Systematic Evolution of Ligands by Exponential Enrichment (SELEX). The function of these aptamers is to bind to HIV-1 PR, inhibit its activity, and thus prevent the replication cycle of the HIV virus. Research has shown that these RNA aptamers have high affinity and specificity, and can non competitively inhibit the protease activity of HIV-1 PR. Through further mutation analysis, researchers identified the secondary structural elements of the ligands crucial for PR binding and demonstrated their ability to inhibit HIV replication in vitro[1].SELEX
In 2015, Duclair S, Gautam A, Ellington A, et al. used an RNA library containing 1014 unique species for screening, and improved their binding ability to HIV-1 PR through nine rounds of SELEX process. After the 10th round of selection, 48 clones were sequenced and four different sequence families were discovered. In order to improve the binding affinity of the first generation RNA adapter, researchers screened variants from a newly generated partially randomized (dosed) pool and conducted an additional eight rounds of selection. Several variants were identified from the 8th round pool of PR10.1 and PR10.9 RNA adapters, and these second-generation PR RNA adapters showed significantly improved binding affinity. Through site-specific mutation analysis, researchers investigated the predicted secondary structure of the second-generation PR10.1-8E RNA adapter to identify structural elements crucial for PR binding[1].
Detailed information are accessible on SELEX page.
Structure
The 2D structure of the figure is based on the article by ribodraw tool to draw. PR10.1-8E aptamer binds to HIV-1 aspartyl protease (PR)[1].5'-GGGUUACCUAGGAGGAGAUGCUCUUAAGUGUAACUUCUCAUAACAUCCGGAGGCUUUUACUUCCGGGGACCUAAGUGACGUCUGAACUGCUUCGAA-3'
Ligand information
SELEX ligand
Aspartyl protease that mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles. Hydrolyzes host EIF4GI and PABP1 in order to shut off the capped cellular mRNA translation. The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response. Also mediates cleavage of host YTHDF3. Mediates cleavage of host CARD8, thereby activating the CARD8 inflammasome, leading to the clearance of latent HIV-1 in patient CD4 T-cells after viral reactivation; in contrast, HIV-1 can evade CARD8-sensing when its protease remains inactive in infected cells prior to viral budding (By similarity).-----from Uniprot| Name | Uniprot ID | Pfam | MW | Amino acids sequences | PDB | Gene ID |
|---|---|---|---|---|---|---|
| HIV-1 protease (PR) | P03366 | PF00077 | 10.792 kDa | PQITLWQRPLVTIKIGGQLKEALLDTGADDTVLEEMSLPGRWKPKMIGGIGGFIKVRQYDQILIEICGHKAIGTVLVGPTPVNIIGRNLLTQIGCTLNF | 4ZIP | AH002345 |
| Name | Sequence | Ligand | Affinity |
|---|---|---|---|
| PR10.1-8E | 5'-GGGUUACCUAGGAGGAGAUGCUCUUAAGUGUAACUUCUCAUAACAUCCGGAGGCUUUUACUUCCGGGGACCUAAGUGACGUCUGAACUGCUUCGAA-3' | HIV-1 protease (PR) | 17 ± 3 nM |
| PR10.1-8A | 5'-GGGUUACCUAGGAGGAGAUGCUCUUAAGUGUAACUUCUCGUAAUUCCCAAGGCUUUUACCUCGGGGUCCUAAGUGACGUCUGAACUGCUUCGAA-3' | HIV-1 protease (PR) | 2.2 ± 0.2 nM |
| PR10.1 | 5'-GGGUUACCUAGGAGGAGAUGCUCUUCAUUGUAACUUCUCAUAAUUUCCCGAGGCUUUUACUUUCGGGGUCCUAAGUGACGUCUGAACUGCUUCGAA-3' | HIV-1 protease (PR) | 115 ± 22 nM |
| PR10.9 | 5'-GGGUUACCUAGGAGGAGAUGCUACAUUACCUAAGUAAGAUUACGGCUUCGAGUUUAGAGACCUCUCCCUGGUAAGUGACGUCUGAACUGCUUCGAA-3' | HIV-1 protease (PR) | 93 ± 19 nM |
| PR10.13 | 5'-GGGUUACCUAGGAGGAGAUGCUCCGGGUCGUCCCCUACGGGGACCUAAAGACUGUGUCCAACCGCCCUCGCCUAAGUGACGUCUGAACUGCUUCGAA-3' | HIV-1 protease (PR) | 154 ± 13 nM |
| PR10.18 | 5'-GGGUUACCUAGGAGGAGAUGCUUCAGACAUUUACCUCACUUCGUCUGUUCAAUCGGGUAACACUCGGGAUGAAAGUGACGUCUGAACUGCUUCGAA-3' | HIV-1 protease (PR) | 140 ± 17 nM |
| PR10.9-8E | 5'-GGGUUACCUAGGAGGAGAUGCUACAUUACCUAGGUAAGAUAACGGCUUCGCGUUCAGAGACCUCUCCCUGGUAAGUGACGUCUGAACUGCUUCGAA-3' | HIV-1 protease (PR) | 22 ± 9 nM |
| PR10.9-8N | 5'-GGGUUACCUAGGAGGAGAUGCUUUGACCUAAGGUAAGAUAACGGCUUCGAGUUCAGAGACCUCGCCCUGGUAAGUGACGUCUGAACUGCUUCGAA-3' | HIV-1 protease (PR) | 4.3 ± 0.2 nM |
Similar compound
We used the Dail server website to compare the structural similarities of ligand proteins, and chose the top 10 in terms of similarity for presentation. The Dali server is a network service for comparing protein structures in 3D. Dali compares them against those in the Protein Data Bank (PDB). Z-score is a standard score that is converted from an original score. The list of neighbours is sorted by Z-score. Similarities with a Z-score lower than 2 are spurious. RMSD(Root Mean Square Deviation) value is used to measure the degree to which atoms deviate from the alignment position.
| PDB | Z-socre | RMSD | Description |
|---|---|---|---|
| 2O40-A | 17.9 | 0.5 | Covalent dimer HIV-1 protease |
| 1B11-A | 15.4 | 1.4 | Protein (feline immunodeficiency virus protease) |
| 1FMB-A | 14.8 | 1.7 | Eiav protease |
| 1BAI-A | 14.1 | 1.9 | Protease |
| 3LIN-B | 13.3 | 2.0 | Protease |
| 6S1V-B | 12.5 | 2.4 | Gag-pro-pol polyprotein |
| 5C9F-A | 10.1 | 2.8 | Aprick protease |
| 3NR6-A | 9.6 | 2.5 | Protease P14 |
| 4Z2Z-B | 9.2 | 2.5 | DNA damage-inducible protein 1 |
| 7KSE-A | 8.7 | 2.7 | Peptidase a9/Reverse transcriptase/Rnase H |
References
[1] High-affinity RNA Aptamers Against the HIV-1 Protease Inhibit Both In Vitro Protease Activity and Late Events of Viral Replication.Duclair, S., Gautam, A., Ellington, A., & Prasad, V. R.
Molecular therapy. Nucleic acids, 4(2), e228. (2015)