Prochiner Marie, Judmann Benedikt, Ruder Alina, Wängler Björn, Schirrmacher Ralf, Wängler Carmen
Biomedical Chemistry, Clinic of Radiology and Nuclear Medicine, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
Research Campus M²OLIE, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany.
Pharmaceuticals (Basel). 2024 Sep 27;17(10):1280. doi: 10.3390/ph17101280.
Affibody molecules represent a class of highly specific binders of particular interest for the development of highly affine target-specific radiopharmaceuticals. Their chemical synthesis is, however, intricate due to their considerable length of 58 amino acids; thus, approaches to optimize their preparation are constantly being sought.
As ultrasound assistance has recently been shown to increase the efficiency of amino acid conjugation during solid-phase peptide synthesis (SPPS), the influence of ultrasonication on the outcome of the SPPS-based preparation of the EGFR-specific affibody Z was compared to a common protocol relying on mechanical shaking.
After the identification of a suitable solid support for the study, the execution of the systematic comparison of both approaches showed that conventional and ultrasound-assisted syntheses yielded equivalent results with analogous composition of the raw products. Further, both approaches produced the affibody in good isolated yields of >20% when applying the same optimal reagent excesses and coupling times for the conjugation of each amino acid. This indicates that, under optimal reaction conditions, the choice of solid support used has a much stronger influence on the outcome of the preparation of Z than the application of ultrasound, which did not further improve the synthesis results.
Therefore, for the chemical synthesis of affibodies, great attention should be paid to the choice of a suitable solid support, enabling this highly interesting class of biomolecules to be obtained in good yields and to bring them more into the focus of radiopharmaceutical research.
亲和体分子是一类高度特异性的结合剂，在开发高亲和力的靶向特异性放射性药物方面具有特殊意义。然而，由于其58个氨基酸的相当长度，其化学合成过程复杂；因此，一直在不断寻求优化其制备方法。
由于最近已证明超声辅助可提高固相肽合成（SPPS）过程中氨基酸偶联的效率，将超声处理对基于SPPS制备表皮生长因子受体（EGFR）特异性亲和体Z的结果的影响与依赖机械振荡的常规方案进行了比较。
在确定适合该研究的固相载体后，对这两种方法进行的系统比较表明，传统合成方法和超声辅助合成方法得到的粗产物组成类似，结果相当。此外，当对每个氨基酸的偶联应用相同的最佳试剂过量和偶联时间时，两种方法都能以大于20%的良好分离产率得到亲和体。这表明，在最佳反应条件下，所用固相载体的选择对Z的制备结果的影响远大于超声处理的应用，超声处理并未进一步改善合成结果。
因此，对于亲和体的化学合成，应高度重视合适固相载体的选择，以使这类极具吸引力的生物分子能够以良好的产率获得，并使其更多地成为放射性药物研究的焦点。
