HIV gag stem loop 3 (GSL3)

HIV gag stem loop 3 (GSL3) is a secondary structural component of the Retroviral Psi packaging element, also known as the psi recognition element. This domain plays a major role in RNA packaging and is located the 5’ untranslated region of the unspliced HIV-1 genome.[1][2][3] GSL3 is known to direct specific packaging of HIV-1 genomic RNA. While deletion of GSL3 leads to decreases in both viral RNA packaging and dimerization, mutagenic studies have shown that it does not eliminate encapsulation of retroviral RNA.[4][5]

HIV gag stem loop 3 (GSL3)
Predicted secondary structure and sequence conservation of HIV_GSL3
Identifiers
SymbolHIV_GSL3
RfamRF00376
Other data
RNA typeCis-reg
Domain(s)Viruses
SOSO:0000233
PDB structuresPDBe

Pharmaceutical Advancements

Interaction with NCp7

RNA encapsulation involves detection of the psi recognition element by the protein NCp7. NCp7 contains two successive zinc fingers which are linked by a stretch of basic residues. Their function is to activate annealing of primer tRNA to the initiation site (where reverse transcription occurs).[6] During this process, GSL3 interacts with NCp7 specifically. Current pharmaceuticals utilized for HIV/AIDS treatment inhibit fundamental processes in the replication cycle of the retrovirus. This interaction is a potential point of inhibition.

Inhibitory Ligands
An example of a lead compound. See [7] for additional information

Inhibitor development remains in an early phase. The challenge of synthesizing a compound with a simple molecular structure and low molecular weight in order to limit side interactions and the existence potentially detrimental stereoisomers requires both a computational and high-throughput approach.[7] 2-((5-nitroquinolin-8-yl)thio)ethanol, a potential lead compound, is shown at right. It is selective for the loop structure of GSL3 over double and single stranded RNA. This implies that if released in a cell targeted by HIV, it would block the stem-loop and thus limit productive interaction with NCp7.[7]

References
  1. Amarasinghe GK, De Guzman RN, Turner RB, Chancellor KJ, Wu ZR, Summers MF (2000). "NMR structure of the HIV-1 nucleocapsid protein bound to stem-loop SL2 of the psi-RNA packaging signal. Implications for genome recognition". J. Mol. Biol. 301 (2): 491–511. doi:10.1006/jmbi.2000.3979. PMID 10926523.
  2. Darlix, JL; Lapadat-Tapolsky, M; de Rocquigny, H; Roques, BP (Dec 8, 1995). "First glimpses at structure-function relationships of the nucleocapsid protein of retroviruses". Journal of Molecular Biology. 254 (4): 523–537. doi:10.1006/jmbi.1995.0635. PMID 7500330.
  3. Dietz J, Koch J, Kaur A, Raja C, Stein S, Grez M, Pustowka A, Mensch S, Ferner J, Möller L, Bannert N, Tampé R, Divita G, Mély Y, Schwalbe H, Dietrich U (2008). "Inhibition of HIV-1 by a peptide ligand of the genomic RNA packaging signal Psi". ChemMedChem. 3 (5): 749–755. doi:10.1002/cmdc.200700194. PMID 18205165.
  4. Damgaard, CK; Andersen, ES; Knudsen, B; Gorodkin, J; Kjems, J (Feb 13, 2004). "RNA interactions in the 5' region of the HIV-1 genome". Journal of Molecular Biology. 336 (2): 369–379. doi:10.1016/j.jmb.2003.12.010. PMID 14757051.
  5. Advances in Hiv-1 Assembly and Release. Springer Verlag. ISBN 978-1-4614-7728-0.
  6. Morellet N, Jullian N, De Rocquigny H, Maigret B, Darlix JL, Roques BP (1992). "Determination of the structure of the nucleocapsid protein NCp7 from the human immunodeficiency virus type 1 by 1H NMR". EMBO J. 11 (8): 3059–3065. PMC 556789. PMID 1639074.
  7. Warui, DM; Baranger, AM (May 10, 2012). "Identification of small molecule inhibitors of the HIV-1 nucleocapsid-stem-loop 3 RNA complex". Journal of Medicinal Chemistry. 55 (9): 4132–4141. doi:10.1021/jm2007694. PMID 22480197.
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