The enduring contributions of Zervas were made together with Bergmann and involved the first successful synthesis of substantial length oligopeptides. They achieved this using the carboxybenzyl amine protecting group for the masking of the N-terminus of the growing oligopeptide chain to which amino acid residues are added in a serial manner. The carboxybenzyl group discovered by Zervas is introduced by reaction with benzyl chloroformate, originally in aqueous sodium carbonate solution at 0 °C:
The protecting group is abbreviated Cbz or, in honour of Zervas, simply Z. The typical route for deprotection involves hydrogenolysis under mild conditions e.g. with hydrogen gas and a catalyst such as palladium on charcoal.
The discovery of the Bergmann-Zervas synthesis has been characterised as "epoch-making" as it allowed the advent of controlled synthetic peptide chemistry, completing the work started in the early 20th century by Bergmann's mentor Emil Fischer. Previously impossible to synthesise oligopeptides with a highly specific sequence and reactive side chains were consequently produced in the 1930s by Bergmann and Zervas. The ability of Z-protection to prevent racemization of activated derivatives of the protected amino acids and the importance thereof were also noted by the two chemists.
Indeed, their method became the standard in the field for the following two decades until further developments in the early 1950s with the introduction of mixed anhydrides (e.g. the Boc group).
Zervas continued his research on peptide synthesis in New York and later in Greece. The first topic of his research once in Greece was the synthesis of N- or O-phosphorylated amino acids, in which he demonstrated the utility of dibenzyl chlorophosphonate. He continued his efforts on the development of new methods within peptide chemistry, including the introduction of the o-nitrophenylsulfenyl (NPS) amino protecting group and peptide synthesis using N-tritylamino acids.
One of the major issues which occupied his interests was the chemical synthesis of insulin after its characterisation by Frederick Sanger (1951). The insulin peptide hormone features two protein chains cross-linked by disulfide bridges from cysteine thiols. For this reason, Zervas undertook a systematic study on asymmetric cysteine-containing peptides. In his attempts he introduced new mercaptan protecting groups (e.g. trityl, benzhydryl or benzoyl), which finally made it possible to produce disulfide bridges in a controlled manner. This was a triumph for peptide chemistry in the lab, but could not be possibly scaled to industrial procedures. Building on this work, the first complete synthesis of insulin was simultaneously achieved in 1963 in RWTH Aachen University by Helmut Zahn and in the University of Pittsburgh by Panayotis Katsoyannis, a student of Zervas. Further work on asymmetrical cysteine polypeptides was also done in Athens by Iphigenia Photaki, another student of his.
Overall, the research work of Zervas spans across six decades (1925–1979) and amounts to 96 publications in international chemistry journals.