Applied  
sciences  
Latest Advances on Synthesis, Purification, and  
Characterization of Peptides and Their Applications  
[PERSON] 1,2,*() [PERSON] 3,4,*() [PERSON] 4,5,6,*()  
Peptides have a broad number of applications: from biochemical tools to diagnostic kits; from nanotechnology to new materials; and from vaccines to drugs. Increased interest in peptides in all these fields is exemplified by the growing number of peptide-based drugs available [1,2]. Table 1 shows the peptide drugs accepted by the US Food and Drug Administration (FDA) between Jan 2015 and May 2021 [3,4]. During these six and a half years, 21 peptide-based drugs have been launched onto the market. This number accounts for approximately 5% of the total number of drugs, including both new chemical entities and biologics, approved by the FDA in the same period. Importantly, although cancer and metabolism continue to be the main target, peptides are being used for a much wider spectrum of indications and they continue to gain applications with time (Table 1). \begin{table}
\begin{tabular}{c c c c} \hline \hline \multirow{2}{*}{**Year**} & **Active Ingredient** & **Indication** & **Characteristics** \\  & **Trade Name** & & & Modified insulin with an aa \\ \hline \multirow{3}{*}{2015} & Insulin degludec & & & \\  & Tresiba\({}^{\text{\tiny{B}}}\) & Diabetes & deletion and a hexadecanedio \\  & & & acid via \(\gamma\)-Glu at Lys (B29) \\ \hline \multirow{3}{*}{2015} & \multirow{3}{*}{
\begin{tabular}{c} Izazomib \\ Ninlar\({}^{\text{\tiny{B}}}\) \\ \end{tabular} } & \multirow{3}{*}{Multiple myeloma} & \(N\)-acylated, C-boronic acid \\  & & & dipeptide \\ \hline \multirow{3}{*}{2016} & Adlyxin & & 44 aa GLP-1 peptide with Lys\({}_{6}\) at the C-terminal \\  & & & & the C-terminal \\ \hline \multirow{3}{*}{2017} & Abaloparatide & & 34 aa analog of parathyroid \\  & Tymlos\({}^{\text{\tiny{B}}}\) & & hormone-related protein \\ \hline \multirow{3}{*}{2017} & Angiotensin II & & \\  & Giapreza\({}^{\text{\tiny{B}}}\) & & \\ \cline{1-1} \cline{2-4}  & & & \\ \cline{1-1} \cline{2-4}  & & & \\ \cline{1-1} \cline{2-4}  & & & \\ \cline{1-1} \cline{2-4}  & & & \\ \cline{1-1} \cline{2-4}  & & & \\ \hline \hline \end{tabular}
\end{table} 
Table 1: Peptide-based drugs approved by the FDA (2015–2021 (May)) [4,5]. Only a few decades ago, it was unthinkable to consider producing an active pharmaceutical ingredient (API) of a chemical entity which requires more than seventy chemical steps--as in the case of Fuzeon(ruftivide, T20) [5]--fulfilling the requirements of the regulatory agencies, targeting both purity of the peptide API and identification of the impurities. This has been possible thanks to the breakthroughs in three fields: (i) chemical synthesis; (ii) purification; and (iii) characterization, which allowed consideration of peptides, and oligonucleotides too, as small molecules from purity and characterization points of view. Coincidentally, at the same time, in the late fifties and early sixties, in the USA East Coast, Nobel Laureate [PERSON] (Rockefeller University, New York) and the entrepreneur [PERSON] (Water Corporation, Milford, Massachusetts, USA) developed two techniques, for synthesis and purification, respectively, that over time proved to be crucial in making peptides and oligonucleotides (TIDES) an alternative to small molecules and biologics as drugs. Interestingly, the two techniques were based on a similar concept, namely the concourse of a solid support--a resin. \begin{table}
\begin{tabular}{c c c c} \hline \hline \multirow{2}{*}{**Year**} & **Active Ingredient** & \multirow{2}{*}{**Indication**} & \multirow{2}{*}{**Characteristics**} \\  & **Trade Name** & & \\ \hline  
Merrifield first envisaged and then implemented a solid polymeric protecting group for the \(C\)-terminal carboxylic group, in the so-called solid-phase peptide synthesis (SPPS) methodology [6]. Thus, the growing peptide chain can be elongated with \(N\)-protected amino acids, while the peptide chain is in a pseudo-soluble state anchored to the solid support (resin).