抗真菌感染新药研究进展

Advances in research on new antifungal drugs

ZHANG Yu ,, CHEN Si-Min, GUO Shi-Yu, HOU Wei-Tong, JIANG Yuan-Ying , ,*, AN Mao-Mao , ,*

Department of Pharmacology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai 200072, China

摘要

随着免疫功能缺陷人群的增多,侵袭性真菌感染（invasive fungal infections,IFIs）的发病率和死亡率逐年上升,严重威胁人类健康。目前临床常用抗侵袭性真菌感染药物有三唑类（氟康唑）、多烯类（两性霉素B）、棘白菌素类（卡泊芬净）等,然而这些药物并不能满足临床需要,侵袭性真菌感染的死亡率仍居高不下。因此,本文着重于目前处于临床研究阶段的抗真菌感染新药,根据作用靶点不同依次介绍：作用于细胞壁的新型葡聚糖合成酶抑制剂CD101和SCY-078、几丁质合成酶抑制剂尼可霉素Z、GPI锚定蛋白抑制剂APX001;作用于细胞膜的CYP51抑制剂VT-1161和VT-1129、破坏细胞膜通透性药物CAmB;影响细胞代谢的嘧啶合成抑制剂F901318,以及生物制剂包括细胞表面凝集素样序列3蛋白疫苗（NDV-3）和抗真菌感染抗体Mycograb。本文主要综述了上述新药的研究进展,包括作用机制、体内外活性、临床研究结果等,为相关药物的研发与未来的临床应用提供参考。

关键词：侵袭性真菌感染;临床研究;抗真菌感染新药;抗真菌靶点;体内外活性

Abstract

The morbidity and mortality of invasive fungal infections (IFIs) are on the increase in recent several years owing to the growing number of immunodeficient patients, and lead to a serious threat to human health. At present, triazoles (fluconazole), polyenes (amphotericin B) and echinocandins (caspofungin), as routine anti-IFIs drugs, are widely administrated in clinical practice. However, the present therapeutic regime in IFIs remains dismal despite decades of efforts in anti-IFIs drugs. Therefore, evaluating the correlation between frontier antifungal drugs and their effects on clinical phases were warranted. In this review, we present various therapeutic targets, including fungal cell wall, cell membrane, cell metabolism, and biological agents. CD101 and SCY-078 inhibiting glucan synthase, nikkomycins Z inhibiting chitin synthase, APX001 inhibiting GPI-anchored protein, VT-1161 and VT-1129 inhibiting fungal CYP51, CAmB disrupting cell membrane permeability, F901318 inhibiting pyrimidine synthesis, cell surface lectin-like sequence 3 protein vaccine (NDV-3) and antifungal infection antibody mycograb were also fully discussed. Besides, this article reviews the research progress of the anti-IFIs drugs as mentioned above, including the functional mechanism, activities in vitro and vivo, outcomes of clinical research, providing an overview of diverse anti-IFIs in the past decades and an outlook for the development of related drugs.

Keywords：invasive fungal infections;clinical studies;new antifungal drugs;antifungal targets;activities in vitro and vivo

近30年来,由于免疫缺陷或受损患者的不断增多（如骨髓移植、免疫抑制剂使用、艾滋病流行、肿瘤放化疗等）、侵入性置管患者的增多（如深静脉营养、机械呼吸等）、胃肠道菌群失调患者的增多（如使用广谱抗生素、胃肠道复杂手术等）,侵袭性真菌感染（IFIs）的发病率一直呈上升趋势。最常见致病真菌包括念珠菌属、新型隐球菌、曲霉菌属引起的侵袭性真菌感染年发病率已经达到十万分之一以上（Pfaller et al. 2006）,其致死率分别达到20%-40%（白念珠菌）、20%-70%（烟曲霉菌）、50%-90%（新型隐球菌）（Butts & Krysan 2012）。与呈明显上升趋势的侵袭性真菌感染相比,抗真菌药物的发展显得十分缓慢,临床安全有效的品种不多。

目前临床上抗侵袭性真菌感染常用药包括三唑类、多烯类、棘白菌素类（Pianalto & Alspaugh 2016）（图1）。三唑类干扰细胞中麦角甾醇的合成从而破坏真菌细胞膜通透性（Campoy & Adrio 2017）,氟康唑主要用于念珠菌血症治疗的备选方案、念珠菌血症的预防及经验性治疗,是隐球菌感染（非中枢）的首选;多烯类靶向真菌细胞膜中的固醇损伤细胞膜通透性从而抑制其生长（Adler-Moore et al. 2016）,两性霉素B（AmB）主要用于新生儿念珠菌病、隐球菌脑膜炎的治疗和曲霉病的替代治疗;棘白菌素类选择性抑制真菌细胞壁上的β-D-1,3-葡聚糖合成从而发挥抗真菌作用,临床上为侵袭性念珠菌感染（粒细胞缺乏、非粒细胞缺乏）患者的首选。然而上述药物并不能满足临床需要,侵袭性真菌感染的死亡率仍居高不下,因此本文将根据作用靶点的不同概述几种抗侵袭性真菌感染新药的研究进展,为相关药物的研发与未来的临床应用提供参考。

图1

图1  抗侵袭性真菌感染药物开发时间轴

Fig. 1  Timeline of anti-IFIs fungal drug developed.

1 以细胞壁为靶点的抗侵袭性真菌感染药物

1.1 新型葡聚糖合成酶抑制剂

棘白菌素通过非竞争性抑制葡聚糖合成酶,阻断几种病原真菌细胞壁内β-D-1,3-葡聚糖的合成,导致真菌细胞壁通透性增加发挥抗真菌作用（Wiederhold 2018）。但是该类药物半衰期短并且耐棘白菌素菌株的出现极大限制了其在临床中的使用（Chang et al. 2017）,为此,Cidara Therapeutics公司和Scynexis公司正在进行新型葡聚糖合成酶抑制剂棘白菌素类CD101和非棘白菌素类SCY-078的临床研究。

1.1.1 CD101：CD101（CidaraTherapeutics,Inc）是最长效的一种棘白菌素类药物（Sandison et al. 2017）,目前正在临床开发中用于治疗念珠菌血症和侵袭性念珠菌病（Lakota et al. 2018）。CD101修饰了环状棘白菌素核心处的胆碱部分（图2A,2B）,导致其在血浆、水溶液和缓冲溶液中的溶解度和稳定性增加（Gonzalez-Lara et al. 2017）,极大地解决了传统棘白菌素类药物半衰期短的问题。CD101与其他棘白菌素类药物的体外抗真菌活性相似,能够有效抑制念珠菌（白念珠菌的MIC50为0.03μg/mL）和曲霉菌（烟曲霉的MEC90为0.015μg/mL）,但对隐球菌无效（Pfaller et al. 2017）。在耳念珠菌感染的中性粒细胞减少性小鼠模型中,血清抑菌浓度-时间曲线下面积（AUC/MIC）预测该药物表现出强效的体内活性（R2=0.76）（Lepak et al. 2018）。I期临床试验中单次和多次递增剂量给药研究的数据分析表明,CD101在健康受试者体内半衰期约为133h（5.5d）（Sandison et al. 2017）,每周一次给药频率的给药方案数据显示,每周给药后雷沙孔菌素有微量蓄积（30%-55%）,两项研究均未发现不良事件（AE）或严重不良事件（SAE）（Lakota et al. 2018）。

1.1.2 SCY-078：SCY-078（Scynexis,Inc.）是天然化合物enfumafungin的半合成衍生物,具有不同于棘白菌素的三萜烯结构（图2C）（Hector & Bierer 2011）,是一种新型的可口服利用的β-1,3-葡聚糖合成酶抑制剂（Scorneaux et al. 2017）,临床开发中该药物通过静脉内和口服给药治疗念珠菌和曲霉菌引起的真菌感染（Wring et al. 2019）。SCY-078具有体外抗念珠菌活性,对大多数FKS（合成β-1,3-葡聚糖合成酶的关键基因）介导的棘白菌素抗性菌株具有较强活性,尤其是对来自白念珠菌和光滑念珠菌的菌株（Jiménez-Ortigosa et al. 2014）。在念珠菌感染的中性粒细胞减少性小鼠模型中,SCY-078显示出针对由WT和棘白菌素抗性光滑念珠菌分离株引起感染的体内功效,能够有效减少肾脏真菌负荷（Wiederhold et al. 2018）。目前SCY-078已经完成两项II期临床试验研究,第一项研究结果表明治疗期间口服SCY-078的急性中重度外阴阴道念珠菌（VVC）感染患者组的临床治愈率高于口服氟康唑组（Helou & Angulo 2017）;第二项研究结果显示SCY-078的安全且耐受良好的口服日剂量为750mg,该剂量的治疗效果与标准治疗相似。两项研究治疗期间均没有发生AE或SAE（Pappas et al. 2017）。

1.2 几丁质合成酶抑制剂

几丁质又称甲壳质、甲壳素,由β-(1,4)-N-乙酰葡糖胺的线性链组成,和β-1,3-葡聚糖共同作为真菌细胞壁的核心多糖（Gow et al. 2017）,其作为真菌细胞壁的特征成分具有潜在毒性小的优势,因此抑制几丁质的合成成为抗真菌药物研究的热点。

尼可霉素Z（Nikkomycin Z,University of Arizona）是天然存在的核苷肽类抗真菌抗生素（图2D）,能够竞争性抑制几丁质合成酶催化UDP-N-乙酰葡糖胺合成几丁质（María Victoria et al. 2014）。尼可霉素Z体内外均有较强抗粗球孢子菌和皮炎芽生菌活性（Hector et al. 1990）,对白念珠菌的分离株有一定活性,但对新生隐球菌、曲霉属和镰刀菌属无效（Li & Rinaldi 1999）,在体内,这种药物已被证明在全身性球孢子菌病和芽生菌病的小鼠模型中的药效优于唑类（Hector et al. 1990;Clemons & Stevens 1997）。然而,尼可霉素Z静脉内和口服给药后的半衰期很短（分别为15min和1h）（Hector et al. 1990）,这将是限制尼可霉素Z临床应用的主要因素。Ⅰ期临床试验研究结果表明,当作为单一口服剂量给予健康受试者时,Nikkomycin Z具有良好的耐受性,且剂量高达2 000mg时未发现剂量相关的AE（Nix et al. 2009）。目前尼可霉素Z进入治疗球孢子菌病的Ⅱ期临床试验,但由于志愿者和资金不足,这项研究提前终止（ClinicalTrials.gov NCT00614666）。

图2

图2  靶向真菌细胞壁抗侵袭性真菌感染药物的化学结构

A：棘白菌素;B：CD101;C：SCY-078;D：尼可霉素Z;E：APX001;F：APX001A

Fig. 2  Chemical structures of anti-IFIs fungal drugs targeting fungal cell wall.

A: Echinocandin; B: CD101; C: SCY-078; D: Nikkomycins Z; E: APX001; F: APX001A.

1.3 GPI锚定蛋白抑制剂

APX001（APX001A的前药,Amplyx Pharmaceuticals,Inc）是一种新靶点抗真菌药物（图2E,2F）,能够选择性抑制真菌的GWT1基因编码的肌醇酰基转移酶Gwt1蛋白,从而阻断糖基磷脂酰肌醇（GPI）合成通路上游的GLcN-PI肌醇酰化反应,抑制GPI锚定蛋白的合成,继而阻止真菌在宿主组织中的粘附和侵袭、菌丝生长、生物膜形成等与真菌毒力相关的生命过程,但对人类GWT1同源基因PIG-W编码的蛋白无抑制作用（Mariko et al. 2003;Watanabe et al. 2012）。

2 以细胞膜为作用靶点的抗侵袭性真菌感染药物

2.1 真菌CYP51抑制剂

真菌细胞膜主要由磷脂类、鞘脂类和固醇组成,为各种功能蛋白提供基质结构,其主要的固醇成分为麦角甾醇,而人细胞膜主要为胆固醇（Sant et al. 2016）。真菌羊毛甾醇-14α-脱甲基酶（CYP51）可催化真菌细胞膜中的羊毛甾醇转化为麦角甾醇,传统唑类药物通过抑制ERG11基因编码的CYP51,抑制麦角甾醇的合成,并使毒性的甾醇产物在真菌细胞中积累,从而抑制真菌的生长与复制（Campoy & Adrio 2017）。然而,传统唑类药物含有结合的咪唑或三唑结构（图3A-3D）,存在抑制人体中CYP51同源酶体的副作用。为解决上述问题,Viamet Pharmaceuticals公司正在开发几种CYP51的金属酶抑制剂,包括含有四唑结构的VT-1161和VT-1129（图3E,3F）,其具有改善的靶向选择性（Hoekstra et al. 2014）,不会与人类CYP51结合（Warrilow et al. 2014;Warrilow et al. 2016）。

图3

图3  靶向真菌细胞膜抗侵袭性真菌感染药物的化学结构

A：伏立康唑;B：艾沙康唑;C：氟康唑;D：泊沙康唑;E：VT-1161;F：VT-1129

Fig. 2  Chemical structures of anti-IFIs drugs targeting fungal cell membrane.

A: Voriconazole; B: Isavuconazole; C: Fluconazole; D: Posaconazole; E: VT-1161; F: VT-1129.

2.1.1 VT-1161：VT-1161比其他氮唑类药物对真菌的CYP51表现出更高的选择性,其中对白念珠菌CYP51的亲和力为Kd≤39nmol/ L,超过了对人体中同源酶体的2 000倍以上（Warrilow et al. 2014）。该药物体内外对白念珠菌（白念珠菌的MIC为0.002μg/mL）、光滑念珠菌和近平滑念珠菌甚至对于抗氟康唑或棘白菌素的分离株均有活性（耐氟康唑菌株的MIC90为0.12μg/mL）,还可有效作用于小鼠的球孢子菌病（球孢子菌的MIC90为2μg/mL）（Warrilow et al. 2014;Garvey et al. 2015）。小鼠体内药动学实验结果显示,VT-1161具有口服生物利用度高（73%）、分布体积广（1.4L/kg）、半衰期长（>48h）等特点（Garvey et al. 2015）。一项评估了VT-1161相较于氟康唑治疗中重度急性VVC患者的疗效和安全性的IIa期临床研究结果显示,VT-1161的临床治愈率与氟康唑相似并具有更高的真菌学治愈率（93% vs. 73%）,随访期间复发率更低,且在该试验中被确定为安全且耐受良好（Brand et al. 2015）。

2.1.2 VT-1129：VT-1129主要表现出对隐球菌的抑制作用（新生隐球菌的MIC90为0.06μg/mL、格特隐球菌的MIC90为0.25μg/mL）（Gray et al. 2012）,对耐氟康唑的新生隐球菌也具有一定的抑制作用（MIC90为2μg/mL）（Nielsen et al. 2017）。VT-1129对隐球菌的CYP51具有选择性抑制作用及强亲和力（IC50范围为0.14-0.2μmol/L,Kd为14-25nmol/L）,对人体中CYP51及同源酶体的抑制作用和亲和力较弱（IC50约为600μmol/L,Kd为4.53μmol/L）（Warrilow et al. 2016）。此外,VT-1129在隐球菌性脑膜炎小鼠模型中显示出改善的功效,在鞘内感染的免疫活性小鼠脑中检测不到隐球菌菌落,并且与氟康唑组相比增加了30d的存活率（Gonzalez-Lara et al. 2017）,在系统性念珠菌病小鼠模型中也显示出强效（Hoekstra et al. 2014）。VT-1129被FDA认定为一种合格的抗感染疾病的产品,用于治疗隐孢子虫性脑膜炎,目前正在美国的健康志愿者中进行Ⅰ期临床试验（Gonzalez-Lara et al. 2017）。

2.2 影响细胞膜通透性的抗侵袭性真菌感染药物

AmB与真菌细胞膜中的麦角甾醇形成复合物,产生跨膜通道,使细胞成分泄漏发挥抗真菌作用（Adler-Moore et al. 2016）,因具有抗真菌活性强和抗菌谱广的优点,曾作为治疗深部真菌感染的唯一药物,被喻为“金标准”。然而严重的肾毒性极大地限制了AmB在临床上的使用（Gray et al. 2012）,为此,Jin et al.（2000）和Zarif（2005）提出制备“纳米耳蜗（nanocochleates）”剂型。“chochleate”药物制剂是基于脂质的药物载体,具备递送疏水性药物如AmB的潜力,并且可以保护相关的“受限”分子免于降解,产生稳定、无毒、高效的AmB脂质颗粒（CAmB,Matinas BioPharma Holdings,Inc）,具有克服AmB口服生物利用度差的优点（Papahadjopoulos et al. 1975;Syed et al. 2008）。CAmB表现出体外抑制烟曲霉（MIC<1μg/mL）与白念珠菌（MIC<1μg/mL）的活性,并且在系统性念珠菌病和侵袭性曲霉菌病的小鼠模型中,口服CAmB可以降低感染小鼠的死亡率和组织的真菌负荷（Santangelo et al. 2000;Delmas et al. 2002）。目前一项评估200mg和400mg剂量的CAmB与单剂量150mg的氟康唑治疗中度至重度VVC的安全性、耐受性和疗效的多中心随机研究已经完成,治疗期间没有SAE发生,400mg剂量CAmB的临床治愈率为单剂量150mg剂量氟康唑的73%（ClinicalTrials.gov NCT02971007）。

3 影响细胞代谢的抗侵袭性真菌感染药物

F901318（F2G Ltd.）是一类抗真菌感染新药（图4）,通过选择性抑制真菌的二氢乳清酸脱氢酶（DHODH,嘧啶生物合成通路中的关键酶,能够催化二氢乳清酸转化为乳清酸）发挥抗真菌作用（Oliver et al. 2016）。尽管哺乳动物体内也存在DHODH,但由于与真菌的同源性较低,F901318在体外对烟曲霉DHODH的抑制作用超过对人体DHODH的2 200倍以上（IC50>100μmol/L）（Oliver et al. 2016）。

图4

图4  F901318的化学结构

Fig. 4  Chemical structure of F901318.

体外研究表明,F901318对丝状和双相真菌具有广谱抑菌活性,包括曲霉菌（烟曲霉的MIC90为0.125μg/mL）（Buil et al. 2017）、唑类抗性曲霉菌株、青霉菌、球孢子菌、荚膜组织胞浆菌、皮肤芽孢杆菌、镰刀菌属和多育赛多孢,但对念珠菌和毛霉等未检测到体外活性（Oliver et al. 2016）。体内研究表明,在侵袭性曲霉病的小鼠模型中,F901318治疗组与未经治疗的对照组和泊沙康唑治疗组相比,表现出显著改善的存活率（Wiederhold et al. 2017）。一项评估输注持续时间对健康志愿者中F901318的耐受性和重复剂量药代动力学的临床研究结果显示,F901318输注持续时间可以安全地减少到1h而不显著增加峰浓度并且仍然达到临床功效的目标阈浓度,治疗期间发生的治疗突发不良事件均为轻度或中度强度,且无SAE（Kennedy et al. 2017）。

4 生物制剂

宿主免疫功能低下是侵袭性真菌感染发生率和死亡率越来越高的主要原因,因此设计有效的疫苗或者抗体是抗真菌领域重要且高效的方法之一（Morrison 2015;Nami et al. 2019）。

4.1 NDV-3

白念珠菌细胞表面凝集素样序列（Als）基因家族包括8个具有共同结构组织的基因,其中Als3的表达与胚管和菌丝的形成有关（Hoyer et al. 1998）。Als3蛋白使钙粘蛋白家族的宿主蛋白粘附到宿主上皮细胞和内皮细胞（Phan et al. 2007）,因此可以通过直接抑制它来清除白念珠菌与上皮细胞的结合。

Als3蛋白疫苗（NDV-3）（NovaDigm Therapeutics,Inc）是一种基于Als3蛋白N端重组片段的疫苗,其通过刺激宿主产生抗Als3蛋白N端抗体增强中性粒细胞介导的调理吞噬作用以杀死白念珠菌（Ibrahim et al. 2013）。BALB/c小鼠通过肌肉或皮下注射接种NDV-3疫苗,与单独接种佐剂作为对照相比,小鼠血清中抗Als3蛋白抗体滴度显著升高（P<0.0001）（Ibrahim et al. 2013）。体内活性研究表明,在白念珠菌感染的小鼠模型中,与单独接种佐剂的感染小鼠相比,接种NDV-3疫苗的感染小鼠增加了60%的存活率（Spellberg et al. 2006）。Ⅱ期临床研究结果表明,NDV-3疫苗对于患有复发性外阴阴道念珠菌病（RVVC）的女性是安全且具有高度免疫原性的,并且在年龄<40岁的女性中将VVC的症状发作频率降低长达12个月（Edwards et al. 2018）。

4.2 Mycograb

热休克蛋白（Hsps）家族在白念珠菌中具有控制基本的生理活性或毒力的生物学功能,其中Hsp90是白念珠菌中研究最深入的Hsps之一,并且许多研究表明破坏白念珠菌的Hsp90能够抑制真菌生长或逆转白念珠菌对传统抗真菌药物的耐受性（Gong et al. 2017）。

Mycograb（NeuTec Pharma plc）是一种针对白念珠菌Hsp90的人类重组抗体,其作为一类抗真菌感染新药旨在与目前最好的抗真菌药物联合使用治疗侵袭性念珠菌病（Bugli et al. 2013）。体外研究表明,Mycograb显示出对最重要的念珠菌属的抗真菌活性,包括对白念珠菌的氟康唑敏感和氟康唑抗性菌株（MIC为128-256μg/mL）,并且与AmB具有协同作用（分数抑制指数为0.09-0.31）;此外,在系统性念珠菌病的小鼠模型中,单剂量2mg/kg的Mycograb与AmB组合减少了平均器官菌落数和阳性活检标本的数量（Matthews et al. 2003）。一项评估成人侵袭性念珠菌病患者AmB脂质剂型加Mycograb是否优于AMB脂质剂型加安慰剂的临床研究结果表明,接受Mycograb治疗的患者清除感染的速度提高了两倍且念珠菌归因死亡率从18%降至4%,但是Mycograb组高血压发生率高于安慰剂组（7.4% vs. 2.9%）（Pachl et al. 2006）。然而,由于Mycograb存在异质性并导致一系列问题,人用药品委员会于2007年3月拒绝对其上市授权（Bugli et al. 2013）,目前关于Mycograb的临床研究均已终止。

5 总结与展望

相较于传统药物,处于临床研发阶段的抗真菌感染新药具有独特优势。它们有的针对新的靶点,例如尼可霉素Z抑制几丁质合成酶,APX001抑制肌醇酰基转移酶Gwt1蛋白,F901318抑制二氢乳清酸脱氢酶,NDV-3靶向白念珠菌Als3蛋白,Mycograb靶向白念珠菌Hsp90蛋白;有的针对已知靶点但具有新的治疗效果,例如SCY-078、CAmB口服可利用,VT-1161和VT-1129通过改造药物结构对真菌CYP51具有更高的选择性从而降低了毒性,CD101通过改造药物结构延长半衰期。这些抗真菌药物上市后对于临床治疗侵袭性真菌感染具有重大意义。

尽管近年来我国真菌感染的基础和临床研究都取得了长足进展,但是自本世纪初棘白菌素类药物卡泊芬净上市后至今,国内外尚未有新作用靶点的药物上市,临床上可选的药物种类少,不能满足需求。我们期待更多基于宿主-真菌二者相互作用过程的抗真菌感染药物的上市,随着研究的深入,我们相信新型抗真菌药物会陆续登上抗感染的舞台,为临床治疗提供更多可行的药物治疗方案。

（本文责编：王敏）

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