Abstract
HIV-1 nucleocapsid (NC) becomes an attractive target for the development of novel anti-HIV-1 agents. Discovering of non-antibody scaffolds that disrupt the function of NC will be a potential aspect for disturbing viral maturation process. Correspondingly, we explored the specific binding site of the thermoresistant-scaffold protein, αRep9A8 which formerly demonstrated the inhibitory effect on HIV-1 replication. The portion of Gag, CA21-SP1-NC has been used as a template for designing nine overlapping peptides (P4–P12). The P9 peptide showed the strongest binding activity followed by P8 and P12 respectively. The amino acid sequences on those peptides resemble the N-terminal domain of the NC proximity to the SP1-NC initial cleavage site and across the conserved CCHC zinc finger 1 (ZF1) of NC. The interaction KD between αRep9A8 with its target was 224.9 ± 57.4 nM. Consequently, αRep9A8 demonstrated the interference of the HIV-1 protease function by hindering a protease cleavage site. The released NC product from CA21-SP1-NC was diminished. The present study provided an additional information of αRep9A8 function in interfering of viral maturation processes resulting in the decremental efficiency of viral infectivity.
Highlights
HIV-1 particle egresses from the plasma membrane of infected cells in an immature particle
The MP0112 (DARPin) (Molecular Partners/Allergen), an ankyrin repeat protein targeting retinal angiogenic disorders driven by vascular endothelial growth factor (VEGF)-A entered Phase III clinical trials in 2015 [22]
We explored the specific binding site of thermoresistant scaffold protein, αRep9A8 using the portion of HIV-1 Gag polyprotein, CA21-spacer peptide 1 (SP1)-NC as a template for designing nine overlapping synthetic short peptides
Summary
HIV-1 particle egresses from the plasma membrane of infected cells in an immature particle. Gag polyprotein is the major component of the viral progeny which requires the proteolytic cleavage to become a mature infectious virus [1]. Maturation process changes the virion morphology from the donut-shaped particle to the conical shaped. Among the five proteolytic cleavage sites on Gag, the rate of cleaving by HIV-1 protease enzyme are different. The fastest cleaving occurs at the SP1–NC junction. Relative to this event, cleaving at SP2-p6 is 9× slower, MA-CA is 14× slower, NC-SP2 is 350× slower, and CA-SP1 is 400× slower [1,2,3]. The proteolytic process allows four major domains of Gag; MA, CA, NC, and p6 to be free and perform its functions
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