Design and Synthesis of HCV-E2 Glycoprotein Epitope Mimics in Molecular Construction of Potential Synthetic Vaccines

Abstract

Hepatitis C virus remains a global threat, despite the availability of highly effective direct-acting antiviral (DAA) drugs. With thousands of new infections annually, the need for a prophylactic vaccine is evident. However, traditional vaccine design has been unable to provide effective vaccines so far. Therefore, alternative strategies need to be investigated. In this work, a chemistry-based approach is explored towards fully synthetic peptide-based vaccines using epitope mimicry, by focusing on highly effective and conserved amino acid sequences in HCV, which, upon antibody binding, inhibit its bio-activity. Continuous and discontinuous epitope mimics were both chemically synthesized based on the HCV-E2 glycoprotein while using designed fully synthetic cyclic peptides. These cyclic epitope mimics were assembled on an orthogonally protected scaffold. The scaffolded epitope mimics have been assessed in immunization experiments to investigate the elicitation of anti-HCV-E2 glycoprotein antibodies. The neutralizing potential of the elicited antibodies was investigated, representing a first step in employing chemically synthesized epitope mimics as a novel strategy towards vaccine design.

Desenho vacinal por imunoinformática contra HCV: Caracterização química e predição de epítopos de células T

“…Assim sendo, ao serem submetidas, as nove proteínas do vírus, conseguiu-se obter que apenas a proteína E2 apresentou sítios de interação com imunoglobulinas E sendo classificada dessa forma como alergênica. Diversas pesquisas demonstram o potencial da glicoproteína E2 como alvo de agentes imunizadores (Deng et al, 2021;El Abd et al, 2011;Meuleman et al, 2021). Porém, como demonstrado na respectiva pesquisa, o software apontou capacidade de ativação de uma possível resposta que prejudicaria a produção da vacina, neste caso, a proteína E2 não se apresenta interessante para compor uma formulação vacinal, pois o intuito da vacina contra o HCV é desenvolver uma resposta TCD8+ eficaz e que não apresente reações adversas, como seria o caso de um possível processo alérgico.…”

Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy, hype or hope?

“…It is shown that protein stability and targeting delivery is enhanced by tuning EGFR ligands and aggregating these ligands 82 . At the same time, a chemical approach was explored based on highly efficient conserved sites of the protein, the use of epitope mimicry to achieve fully synthetic peptides, which mimic amino acid sequences that inhibit their biological activity when bound to antibodies 83 , 84 . They also have a high bioavailability, and stablility in vivo .…”

From Structural Studies to HCV Vaccine Design

“…Over the past decade, several vaccine-design strategies have been proposed and evaluated for the induction of HCV bnAbs. These strategies include: (a) removal and suppression of immunodominant decoy epitope (see Section 2.3.3 ) [ 136 , 138 , 139 , 140 ]; (b) grafting of neutralizing epitopes onto heterologous scaffolds [ 144 , 145 , 146 , 147 ]; (c) stabilizing antigen structures [ 144 , 148 , 149 , 150 ]; and (d) presenting neutralizing epitopes on nanoparticles [ 32 , 144 , 151 ].…”

“…The designing of a fully synthetic peptide-based antigen, using an epitope mimicry strategy, was recently reported [ 146 ]. Cyclic epitopes were chemically synthesized based on AS412, AS434, and epitope III.…”