Rational Design, Synthesis and Biological Evaluation of Benzimidazoles; Towards a Novel Therapy Selectively Targeting C. neoformans beta-tubulin

苯并咪唑类药物的合理设计、合成及生物学评价；

• 批准号: MR/N023005/1
• 负责人: Gemma Nixon
• 金额: $ 54.22万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN023005%2F1
• 关键词: Rational; Design; Synthesis; Biological; Evaluation

The Need:Cryptococcus neoformans (C. neoformans) is a yeast like fungus which manifests as meningitis and less frequently pneumonia within the human body. In sub-Saharan Africa C. neoformans causes more deaths annually than tuberculosis. C. neoformans is the most common cause of fungal infection in patients with AIDS and there are an estimated 1 million cases of cryptococcal meningitis worldwide each year. The current drugs used to treat this disease are a 2 week course of amphotericin B and 5-flucytosine followed by a long term course of fluconazole. Amphotericin B and 5-flucytosine are associated with toxicity and fluconazole suppresses the growth of the fungus but does not completely remove it from the body. There is a therefore a great need for new drugs to treat C. neoformans infections. These drugs must have less toxicity and work better against the disease. The aim of this proposal is to complete the early stage drug discovery activities required to ultimately develop new drugs for cryptococcal meningoencephalitis that can be used in sub-Saharan Africa.The Concept:It has previously been reported within scientific papers that a class of compound called the benzimidazoles (widely used to treat worm infections in humans and as fungicides in agriculture) have good activity against C. neoformans in a laboratory and this has subsequently been confirmed by work here at the University of Liverpool (UoL). Benzimidazoles have been shown to interfere with cell division in C. neoformans through binding to beta-tubulin. Beta-tubulin is a protein that is essential for cell division and growth, when benzimidazoles bind to beta-tubulin the fungal cell can no longer grow. More recently, unpublished studies carried out at UoL have shown flubendazole to be active against C. neoformans in the mouse model. Humans also have beta-tubulin so it is essential that any new drug developed against the beta-tubulin target is selective for C. neoformans beta-tubulin. Medicinal chemistry (modification of the chemical structure of a drug) can be used to improve both selectivity for beta-tubulin and activity against C. neoformans.The Solution:Identification of an active class of compound, against a known target, with established whole cell C. neoformans and animal model activity provides an excellent starting point for medicinal chemistry modification. To date benzimidazole compounds have never undergone medicinal chemistry optimisation to establish beta-tubulin selectivity or to improve C. neoformans activity. The two most commonly use benzimidazole drugs (Flubendazole and albendazole) are extensively metabolised within the body and have a limited ability to move from the stomach into the blood stream. New compounds will be designed using information from computer models to predict how they are likely to behave within the body. In order to improve the safety profile of the newly designed compounds their selectivity for C. neoformans beta-tubulin over human beta-tubulin will be measured in the laboratory (alongside activity against C. neoformans) and computer models of the binding sites of the two tubulins used to look at how new compounds are likely to bind better with C. neoformans beta-tubulin. Once C. neoformans activity, selectivity for beta-tubulin and improved levels of circulating drug have been established the compounds will move into a mouse model of C. neoformans infection. Impact:The long term aim is to develop a single therapy that does not require subsequent long term treatment with fluconazole and that can be given both orally and by injection. Given the number of patients affected by C. neoformans this project has the potential to have a dramatic beneficial impact on individuals and societies.Development:Compounds demonstrating activity in the mouse model will form the basis of further funding applications to progress the new drugs through the drug development pipeline.

需求：新型隐球菌（C. neoformans）是一种酵母菌状真菌，在人体内表现为脑膜炎和较少见的肺炎。在撒哈拉以南非洲，每年因新生梭状芽孢杆菌死亡的人数超过结核病。新生隐球菌是艾滋病患者真菌感染的最常见原因，全世界每年估计有100万例隐球菌脑膜炎病例。目前用于治疗这种疾病的药物是两性霉素B和5-氟胞嘧啶的2周疗程，然后是氟康唑的长期疗程。两性霉素B和5-氟胞嘧啶与毒性有关，氟康唑抑制真菌的生长，但不能完全将其从体内清除。因此，迫切需要新的药物来治疗新生梭状菌感染。这些药物必须毒性更小，对疾病的疗效更好。该提案的目的是完成所需的早期药物发现活动，最终开发可在撒哈拉以南非洲使用的隐球菌性脑膜脑炎新药。概念：以前在科学论文中报道过，一类被称为苯并咪唑的化合物（广泛用于治疗人类蠕虫感染和农业杀菌剂）在实验室中对新生梭状芽胞杆菌具有良好的活性，随后在利物浦大学（UoL）的研究中证实了这一点。苯并咪唑已被证明通过与β -微管蛋白结合而干扰新生巨噬细胞的细胞分裂。-微管蛋白是一种对细胞分裂和生长至关重要的蛋白质，当苯并咪唑与-微管蛋白结合时，真菌细胞就不能再生长。最近，在UoL进行的未发表的研究表明，氟苯达唑对小鼠模型中的新生梭状芽胞杆菌有活性。人类也有β -微管蛋白，因此任何针对β -微管蛋白靶点开发的新药都必须对新生C. β -微管蛋白具有选择性。药物化学（修饰药物的化学结构）可用于提高β -微管蛋白的选择性和抗新生梭状菌的活性。解决方案：识别一类活性化合物，针对已知靶标，具有已建立的全细胞新生C.和动物模型活性，为药物化学修饰提供了一个极好的起点。迄今为止，苯并咪唑化合物从未经过药物化学优化以建立β -微管蛋白选择性或提高新生梭菌的活性。两种最常用的苯并咪唑类药物（氟苯达唑和阿苯达唑）在体内被广泛代谢，从胃进入血液的能力有限。新化合物的设计将利用计算机模型的信息来预测它们在体内的表现。为了提高新设计的化合物的安全性，将在实验室中测量它们对新生C. β -微管蛋白的选择性（以及对新生C.的活性）和两种微管蛋白结合位点的计算机模型，以观察新化合物如何可能更好地与新生C. β -微管蛋白结合。一旦确定了新生C.的活性、β -微管蛋白的选择性和循环药物水平的提高，这些化合物将进入新生C.感染的小鼠模型。影响：长期目标是开发一种不需要氟康唑长期治疗的单一疗法，可口服或注射。考虑到受新生芽胞杆菌影响的患者数量，该项目有可能对个人和社会产生巨大的有益影响。开发：在小鼠模型中显示出活性的化合物将成为进一步资助应用的基础，从而通过药物开发管道推进新药的开发。

项目成果

Population pharmacokinetics of liposomal amphotericin B in adults with HIV-associated cryptococcal meningoencephalitis.

• DOI: 10.1093/jac/dkac389
• 发表时间: 2022-12-23
• 期刊: The Journal of antimicrobial chemotherapy

Population pharmacokinetics and CSF penetration of flucytosine in adults with HIV-associated cryptococcal meningoencephalitis.

• DOI: 10.1093/jac/dkad038
• 发表时间: 2023-04-03
• 期刊: JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY
• 影响因子: 5.2
• 作者: Stott, Katharine E.;Ahmadu, Ajisa;Kajanga, Cheusisime;Moyo, Melanie;Gondwe, Ebbie;Chimang'anga, Wezzie;Chasweka, Madalitso;Unsworth, Jennifer;Jimenez-Valverde, Ana;Jagota, Bhavana;Shah, Reya, V;Lawrence, David S.;Lalloo, David G.;Harrison, Tom;Jarvis, Joseph N.;Hope, William;Mwandumba, Henry C.
• 通讯作者: Mwandumba, Henry C.

Efficacy of APX2039 in a Rabbit Model of Cryptococcal Meningitis.

• DOI: 10.1128/mbio.02347-22
• 发表时间: 2022-12-20
• 期刊: MBIO
• 影响因子: 6.4
• 作者: Giamberardino, Charles D.;Schell, Wiley A.;Tenor, Jennifer L.;Toffaletti, Dena L.;Palmucci, Julia R.;Marius, Choiselle;Boua, Jane-Valeriane K.;Soltow, Quinlyn;Mansbach, Robert;Moseley, M. Arthur;Thompson, J. Will;Dubois, Laura G.;Hope, William;Perfect, John R.;Shaw, Karen Joy
• 通讯作者: Shaw, Karen Joy

Single-Dose Liposomal Amphotericin B Treatment for Cryptococcal Meningitis.

• DOI: 10.1056/nejmoa2111904
• 发表时间: 2022-03-24
• 期刊: The New England journal of medicine
• 作者: Jarvis JN;Lawrence DS;Meya DB;Kagimu E;Kasibante J;Mpoza E;Rutakingirwa MK;Ssebambulidde K;Tugume L;Rhein J;Boulware DR;Mwandumba HC;Moyo M;Mzinganjira H;Kanyama C;Hosseinipour MC;Chawinga C;Meintjes G;Schutz C;Comins K;Singh A;Muzoora C;Jjunju S;Nuwagira E;Mosepele M;Leeme T;Siamisang K;Ndhlovu CE;Hlupeni A;Mutata C;van Widenfelt E;Chen T;Wang D;Hope W;Boyer-Chammard T;Loyse A;Molloy SF;Youssouf N;Lortholary O;Lalloo DG;Jaffar S;Harrison TS;Ambition Study Group
• 通讯作者: Ambition Study Group

Repurposing and Reformulation of the Antiparasitic Agent Flubendazole for Treatment of Cryptococcal Meningoencephalitis, a Neglected Fungal Disease.

• DOI: 10.1128/aac.01909-17
• 发表时间: 2018-04
• 期刊: Antimicrobial agents and chemotherapy
• 影响因子: 4.9
• 作者: Nixon GL;McEntee L;Johnson A;Farrington N;Whalley S;Livermore J;Natal C;Washbourn G;Bibby J;Berry N;Lestner J;Truong M;Owen A;Lalloo D;Charles I;Hope W
• 通讯作者: Hope W