Evaluating the potential of non-immunosuppressive cyclosporin analogs for targeting Toxoplasma gondii cyclophilin: Insights from structural studies.

IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Protein Science Pub Date : 2024-10-01 DOI:10.1002/pro.5157
Filippo Favretto, Eva Jiménez-Faraco, Gianluca Catucci, Adele Di Matteo, Carlo Travaglini-Allocatelli, Sheila J Sadeghi, Paola Dominici, Juan A Hermoso, Alessandra Astegno
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引用次数: 0

Abstract

Toxoplasmosis persists as a prevalent disease, facing challenges from parasite resistance and treatment side effects. Consequently, identifying new drugs by exploring novel protein targets is essential for effective intervention. Cyclosporin A (CsA) possesses antiparasitic activity against Toxoplasma gondii, with cyclophilins identified as possible targets. However, CsA immunosuppressive nature hinders its use as an antitoxoplasmosis agent. Here, we evaluate the potential of three CsA derivatives devoid of immunosuppressive activity, namely, NIM811, Alisporivir, and dihydrocyclosporin A to target a previously characterized cyclophilin from Toxoplasma gondii (TgCyp23). We determined the X-ray crystal structures of TgCyp23 in complex with the three analogs and elucidated their binding and inhibitory properties. The high resolution of the structures revealed the precise positioning of ligands within the TgCyp23 binding site and the details of protein-ligand interactions. A comparison with the established ternary structure involving calcineurin indicates that substitutions at position 4 in CsA derivatives prevent calcineurin binding. This finding provides a molecular explanation for why CsA analogs can target Toxoplasma cyclophilins without compromising the human immune response.

评估非免疫抑制性环孢素类似物靶向弓形虫嗜环蛋白的潜力:结构研究的启示。
弓形虫病一直是一种流行病,面临着寄生虫抗药性和治疗副作用的挑战。因此,通过探索新的蛋白质靶点来确定新的药物对于有效干预至关重要。环孢素 A(CsA)对刚地弓形虫具有抗寄生虫活性,环嗜蛋白被确定为可能的靶点。然而,CsA 的免疫抑制特性阻碍了它作为抗弓形虫药物的使用。在这里,我们评估了三种不具有免疫抑制活性的 CsA 衍生物(即 NIM811、Arisporivir 和双氢环孢子素 A)靶向一种之前已表征过的刚地弓形虫嗜环蛋白(TgCyp23)的潜力。我们测定了 TgCyp23 与这三种类似物复合物的 X 射线晶体结构,并阐明了它们的结合和抑制特性。高分辨率的晶体结构揭示了配体在 TgCyp23 结合位点中的精确定位以及蛋白质与配体相互作用的细节。与钙调素三元结构的比较表明,CsA 衍生物中第 4 位的取代会阻止钙调素的结合。这一发现从分子上解释了为什么 CsA 类似物可以靶向弓形虫环嗜蛋白而不损害人类免疫反应。
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来源期刊
Protein Science
Protein Science 生物-生化与分子生物学
CiteScore
12.40
自引率
1.20%
发文量
246
审稿时长
1 months
期刊介绍: Protein Science, the flagship journal of The Protein Society, is a publication that focuses on advancing fundamental knowledge in the field of protein molecules. The journal welcomes original reports and review articles that contribute to our understanding of protein function, structure, folding, design, and evolution. Additionally, Protein Science encourages papers that explore the applications of protein science in various areas such as therapeutics, protein-based biomaterials, bionanotechnology, synthetic biology, and bioelectronics. The journal accepts manuscript submissions in any suitable format for review, with the requirement of converting the manuscript to journal-style format only upon acceptance for publication. Protein Science is indexed and abstracted in numerous databases, including the Agricultural & Environmental Science Database (ProQuest), Biological Science Database (ProQuest), CAS: Chemical Abstracts Service (ACS), Embase (Elsevier), Health & Medical Collection (ProQuest), Health Research Premium Collection (ProQuest), Materials Science & Engineering Database (ProQuest), MEDLINE/PubMed (NLM), Natural Science Collection (ProQuest), and SciTech Premium Collection (ProQuest).
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