Jana Asis K, Greenwood Augustus B, Hansmann Ulrich H E
Department of Chemistry & Biochemistry, University of Oklahoma, Norman, Oklahoma 73019, United States.
ACS Med Chem Lett. 2021 Oct 5;12(10):1613-1621. doi: 10.1021/acsmedchemlett.1c00456. eCollection 2021 Oct 14.
Deposition of human serum amyloid A (SAA) amyloids in blood vessels, causing inflammation, thrombosis, and eventually organ damage, is commonly seen as a consequence of certain cancers and inflammatory diseases and may also be a risk after SARS-COV-2 infections. Several attempts have been made to develop peptide-based drugs that inhibit or at least slow down SAA amyloidosis. We use extensive all-atom molecular dynamic simulations to compare three of these drug candidates for their ability to destabilize SAA fibrils and to propose for the best candidate, the N-terminal sequence SAA1-5, a mechanism for inhibition. As the lifetime of peptide drugs can be increased by replacing l-amino acids with their mirror d-amino acids, we have also studied corresponding d-peptides. We find that DRI-SAA1-5, formed of d-amino acids with the sequence of the peptide reversed, has similar inhibitory properties compared to the original l-peptide and therefore may be a promising candidate for drugs targeting SAA amyloidosis.
人血清淀粉样蛋白A（SAA）淀粉样物质在血管中沉积，引发炎症、血栓形成，并最终导致器官损伤，这在某些癌症和炎症性疾病中很常见，在感染SARS-CoV-2后也可能存在风险。人们已多次尝试开发基于肽的药物来抑制或至少减缓SAA淀粉样变性。我们使用广泛的全原子分子动力学模拟来比较三种这类候选药物破坏SAA纤维稳定性的能力，并为最佳候选药物N端序列SAA1-5提出一种抑制机制。由于用镜像d-氨基酸取代l-氨基酸可以延长肽类药物的寿命，我们还研究了相应的d-肽。我们发现，由序列颠倒的d-氨基酸组成的DRI-SAA1-5与原始的l-肽具有相似的抑制特性，因此可能是治疗SAA淀粉样变性的有前景的候选药物。
