Abstract
The broadly neutralizing antibody PG9 recognizes a unique glycopeptide epitope in the V1V2 domain of HIV-1 gp120 envelope glycoprotein. The present study describes the design, synthesis, and antibody-binding analysis of HIV-1 V1V2 glycopeptide-Qβ conjugates as a mimic of the proposed neutralizing epitope of PG9. The glycopeptides were synthesized using a highly efficient chemoenzymatic method. The alkyne-tagged glycopeptides were then conjugated to the recombinant bacteriophage (Qβ), a virus-like nanoparticle, through a click reaction. Antibody-binding analysis indicated that the synthetic glycoconjugates showed significantly enhanced affinity for antibody PG9 compared with the monomeric glycopeptides. It was also shown that the affinity of the Qβ-conjugates for antibody PG9 was dependent on the density of the glycopeptide antigen display. The glycopeptide-Qβ conjugates synthesized represent a promising candidate of HIV-1 vaccine.
Highlights
A protective vaccine is the best hope to combat the global epidemic of HIV/AIDS
We have previously identified a cyclic glycopeptide epitope derived from the HIV-1 ZM109 strain carrying a Man5GlcNAc2 and a sialylated complex type N-glycan at the N160 and N173 site, respectively, as a minimal neutralizing epitope that demonstrate the specificity for antibody PG9, which demonstrate a μM-level affinity for the Fab domain of the antibody [25]
The precursor GlcNAc-peptides were synthesized through microwave-assisted solid-phase peptide synthesis (MW-SPPS) using Fmoc chemaisntdryNo1n7R3isnikteAs,mtwidoe oRretshiong. oTnoailnlsytaplrlodtiefcfetreednGt glclyNcAancs-AatsnthbeuNil1d6i0nganbdloNck17s,3is.eit.e, sa,ctiwd-olabile FOoAbmruHstinhold(ocbDi-gunAEoigInslPdnabSi(llnlD3oyGgcEklcIbPNp(lS2orA)o3cGctkwe)l-cc(eOt2NreHe)dAwibnceu)sG-triOaleldclHlNiienndAbgstucaba-itlAlloldteschidnkneg(ap1btbr)leutoadhincleedkdtiep(nbr1rgma)esdaienn-ebeldtadleobbrciNmlakes-sigeF,n-lmeyladciob.oecisN.l,yeA-lFgasntmaliy-co(oicnAdoc-c-sslA3ayiGtblsealincltNe-Ni(oA1An6cFc03s)mG-iaOtonelcHcdN-NA16c0)aNn1d73N, r1e7s3p,ecrteisvpeelyc,tifvoellloyw, ifnoglloowurinpgrevoiuorusplyrerveipoourstelyd rperpocoerdteudrep[r4o4c] e(Sdcuhreem[e441]).(GSclohbeaml e 1)
Summary
A protective vaccine is the best hope to combat the global epidemic of HIV/AIDS. Despite tremendous efforts, an effective immunogen capable of eliciting long-lasting, broadly neutralizing antibodies (bNAbs) has yet to be realized [1,2,3,4,5,6,7,8,9,10]. Haynes and coworkers have reported that a 30-mer synthetic mini-V3 glycopeptide derived from the JR-FL strain, when formulated in the Toll-like receptor 4 agonist GLA-SE adjuvant, can induce V3-glycan targeted antibodies in rhesus macaques, the monomeric V3 glycopeptide lacking T-helper epitopes are weakly immunogenic require high-dose and long repeated immunization to raise glycan-specific antibodies [31,32]. Despite these encouraging immunization results, the synthesis of the three-component glycopeptide immunogens takes multiple steps and is not easy to make. The results suggest that the synthetic conjugates may serve as a valuable HIV vaccine candidate for raising HIV-1 glycopeptide-specific antibodies
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