CN105394046B - 用于抑制昆虫宿主感觉的组合物 - Google Patents
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- CN105394046B CN105394046B CN201510683406.9A CN201510683406A CN105394046B CN 105394046 B CN105394046 B CN 105394046B CN 201510683406 A CN201510683406 A CN 201510683406A CN 105394046 B CN105394046 B CN 105394046B
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- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/647—Triazoles; Hydrogenated triazoles
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- A—HUMAN NECESSITIES
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- A01M—CATCHING, TRAPPING OR SCARING OF ANIMALS; APPARATUS FOR THE DESTRUCTION OF NOXIOUS ANIMALS OR NOXIOUS PLANTS
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- A—HUMAN NECESSITIES
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- A01M—CATCHING, TRAPPING OR SCARING OF ANIMALS; APPARATUS FOR THE DESTRUCTION OF NOXIOUS ANIMALS OR NOXIOUS PLANTS
- A01M1/00—Stationary means for catching or killing insects
- A01M1/20—Poisoning, narcotising, or burning insects
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- A01M1/2016—Poisoning insects using bait stations for flying insects
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- A—HUMAN NECESSITIES
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- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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Abstract
本发明提供昆虫嗅觉受体的化学调节剂。特别是,提供能够抑制例如蚊虫等昆虫的宿主靶向功能的化合物和组合物。还提供使用这些药剂的方法,以及包含这些药剂的物品。
Description
本申请是申请日为2011年10月21日、申请号为201180062303、发明名称为“用于抑制昆虫宿主感觉的组合物”的申请的分案申请。
本申请要求2010年10月25日提交的美国临时申请序列号61/406,368和2010年10月26日提交的美国临时申请序列号61/406,786的优先权权益,所述两文献的全部内容据此以引用的方式并入。
技术领域
本发明涉及昆虫学和传染病领域。本发明更尤其是涉及用于破坏蚊虫和其他昆虫的宿主靶向的方法和组合物。
背景技术
充当农业害虫和疾病媒介物的昆虫分别导致异常的经济和医学影响。人类疟疾影响着超过二十亿人的住宅区域,并且每年引起至少一百万例死亡。这种疾病对社会和经济的影响是惊人的,有相当一部分的死亡人数属于5岁或不到5岁的儿童。并且,尽管在上一世纪的后半叶,对限制这种疾病取得了成功,但最近的趋势显示某些地区的疟疾感染有复发现象,并且暗示着以疟疾传输的模式发生转变。
目前,预防疟疾传播的主要手段是使用杀灭蚊媒的杀昆虫剂。然而,各种形式的杀昆虫剂处理—室内残留喷洒、杀昆虫剂处理过的衣物、被褥和网织物以及化学杀幼虫剂处理—各自具有缺陷,包括环境和宿主毒性、有限的持续时间以及需要接触昆虫。生物学杀幼虫剂处理可以避免毒性问题,但是耗费时间,并且代价相当高。化学预防同样代价高并且会具有不可接受的副作用。最后,分离群体的代价高并且在多数情况下(世界上发展中国家)不切实际。
因此,尽管有许多不同的方式来攻击疟疾并且各自实质上有助于限制疾病传播,但它们各自还具有局限性,这些为实质改善留有余地。
发明内容
因此,根据本发明,提供一种破坏昆虫寻找宿主的行为的方法,其包括向昆虫环境提供结合于和/或促进昆虫Orco离子通道(先前在冈比亚按蚊(Anopheles gambiae)中称为AgOR7,但在本文中以同义词来提及)的化合物。所述昆虫可以是库蚊(Culcine mosquito)或按蚊(Anopheline mosquito)、双翅目(Dipteran)、鳞翅目(Lepidopteran)或蜱亚目(Ixodida)昆虫。其他农业有害昆虫包括叶甲属(Acalymma)、花园玫瑰卷叶蛾(Aclerisvariegana)、非洲粘虫、非洲化蜜蜂、潜蝇科(Agromyzidae)、布朗夜蛾(Agrotis munda)、变异夜蛾(Agrotis porphyricollis)、吴刺粉虱(Aleurocanthus woglumi)、甘蓝粉虱(Aleyrodes proletella)、南瓜缘蝽(Anasa tristis)、奥地利丽金龟(Anisopliaaustriaca)、苹果开花象鼻虫(Anthonomus pomorum)、草莓花象(Anthonomus signatus)、红圆蚧(Aonidiella aurantii)、蚜虫、甜菜蚜(Aphis fabae)、棉蚜(Aphis gossypii)、苹实蝇(Apple maggot)、阿根廷蚁(Argentine ant)、原切根虫(Army cutworm)、山龙眼蛾(Arotrophora arcuatalis)、咖啡链蚧(Asterolecanium coffeae)、澳大利亚灾蝗、马铃薯木虱(Bactericera cockerelli)、果实蝇属(Bactrocera)、番石榴实蝇(Bactroceracorrecta)、蓓蝽(Bagrada hilaris)、胡桃天牛(Banded hickory borer)、班克木钻孔蛾(Banksia Boring Moth)、甜菜夜蛾、亚澳白裙夜蛾(Bogong moth)、棉铃象虫(Bollweevil)、甘蓝蚜(Brevicoryne brassicae)、褐飞蝗、棕色大理石纹蝽、稻褐飞虱、小菜蛾、菜粉蝶幼虫、四纹豆象(Callosobruchus maculates)、甘蔗甲虫、胡萝卜茎蝇、瘿蚊科(Cecidomyiidae)、地中海实蝇(Ceratitis capitata)、黑角负泥虫、大麦条足秆蝇(Chlorops pumilionis)、柑橘长角虫、咖啡绿软蚧(Coccus viridis)、苹果蠹蛾、咖啡虎天牛甲虫、马铃薯甲、杂拟谷盗(Confused flour beetle)、草螟属(Crambus)、黄瓜叶甲(Cucumber beetle)、象鼻虫(Curculio nucum)、小地老虎(Dark Sword-grass)、沙枣核甲虫、根蝇(属)(Delia)、葱地种蝇(Delia antique)、萝卜地种蝇(Delia floralis)、甘蓝地种蝇(Delia radicum)、沙漠蝗、根萤叶甲属(Diabrotica)、小菜蛾(Diamondback moth)、瓜绢野螟(Diaphania indica)、黄瓜绢野螟(Diaphania nitidalis)、柑桔木虱(Diaphorinacitri)、蔗根非耳象(Diaprepes abbreviates)、长额负蝗(Differential grasshopper)、摩洛哥戟纹蝗(Dociostaurus maroccanus)、樱桃果蝇(Drosophila suzukii)、香蕉弄蝶(Erionota thrax)、绵蚜亚科(Eriosoniatinae)、岛屿甘蔗飞虱(Eumetopina flavipes)、欧洲玉米螟(European corn borer)、洋芜青油菜蝽(Eurydema oleracea)、麦扁盾蝽(Eurygaster integriceps)、森林红蝽、西花蓟马(Frankliniella occidentalis)、东花蓟马(Fankliniella tritici)、大蜡螟(Galleria mellonella)、黑切根虫(Garden Dart)、温室粉虱、东方蝼蛄(Gryllotalpa orientalis)、黑蟋蟀(Gryllus pennsylvanicus)、舞毒蛾(Gpsy moth)、棉铃虫(Helicoverpa armigera)、谷实夜蛾(Helicoverpa zea)、茄二十八星瓢虫(Henosepilachna vigintioctopunctata)、小麦瘿蚊、日本丽金龟、谷斑皮蠹、亮灰蝶(Lampides boeticus)、潜叶虫、表親擬甘蔗跳甲(Lepidiota consobrina)、苹果贝蚧(Lepidosaphes ulmi)、叶足啄缘蝽(Leptoglossus zonatus)、草地盲蝽(Leptopternadolabrata)、小蜡螟(Lesser wax moth)、银潜蛾属(Leucoptera)(蛾虫)、咖啡小扇潜蛾(Leucoptera caffeine)、苹褐卷叶蛾、稻水象(Lissorhoptrus oryzophilus)、长尾弄蝶、草盲蝽(Lygus)(属)、豆荚草盲蝽(Lygus hesperus)、桑粉介壳虫(Maconellicoccushirsutus)、蔷薇鳃角金龟(Macrodactylus subspinosus)、马铃薯长管蚜(Macrosiphumeuphorbiae)、玉米象、烟草天蛾(Manduca sexta)、大麦杆瘿蚊(Mayetiola hordei)、水蜡虫、筛豆龟蝽(Megacopta cribraria)、蛾虫、葱谷蛾、桃蚜(Myzus persicae)、稻绿蝽(Nezara viridula)、油橄榄实蝇、禾蝇科(Opomyzidae)、非洲达摩凤蝶(Papiliodemodocus)、木瓜粉蚧(Paracoccus marginatus)、叶状虫胶介壳虫(Paratachardinapseudolobata)、豆长管蚜、盾蝽总科(Pentatomoidea)、马铃薯块茎蛾(Phthorimaeaoperculella)、鳃角金龟(Phyllophaga)(属)、葡萄根瘤蚜(Phylloxera)、根瘤蚜总科(Phylloxeroidea)、欧洲粉蝶(Pieris brassicae)、棉红铃虫(pink bollworm)、小卷叶蛾(Platynota idaeusalis)、梅象(Plum curculio)、暗色粉蚧(Pseudococcus viburni)、紫斑谷螟(Pyralis farinalis)、红火蚁(Red imported fire ant)、红翅蝗、樱桃绕实绳(Rhagoletis cerasi)、西部樱桃实蝇(Rhagoletis indifferens)、越橘绕实蝇(Rhagoletis mendax)、玉米缢管蚜(Rhopalosiphum maidis)、红棕象甲(Rhynchophorusferrugineus)、谷蠹(Rhyzopertha dominica)、米蛾、俄罗斯小麦蚜虫、梨圆蚧、眼蕈蚊科(Sciaridae)、茶黄蓟马(Scirtothrips dorsalis)、盾蝽科(Scutelleridae)、蛇纹潜叶虫、银斑夜蛾(Silver Y)、银叶粉虱(Silverleaf whitefly)、小蜂房甲虫、大豆蚜(Soybeanaphid)、深斑柳蛾(Spodoptera cilium)、斜纹夜蛾(Spodoptera litura)、十一星瓜叶甲、南瓜藤透翅蛾、二斑姬缘蝽(Stenotus binotatus)、胸喙亚目(Sternorrhyncha)、红向日葵种子象鼻虫(Strauzia longipennis)、黄宽条跳甲、麦扁盾蝽(Sunn pest)、菲缘蝽(Sweetpotato bug)、牧草盲蝽(Tarnished plant bug)、蓟马(Thrips)(属)、南黄蓟马(Thrips palmi)、褐色桔蚜(Toxoptera citricida)、非洲木虱(Trioza erytreae)、番茄斑潜蝇(Tuta absoluta)、小园皮蠹、黄星小灰蝶(Virachola isocrates)、蜡虫(Waxworm)、西方玉米根虫(Western corn rootworm)、小麦蝇(Wheat fly)、小麦象鼻虫(Wheat weevil)、冬尺蠖(Winter Moth)以及石果材小蠹(Xyleborus glabratus)。在一些实施方案中,所述昆虫可以为作物害虫。在另一些实施方案中,所述昆虫可以为气传昆虫(airborneinsect)。在又一些实施方案中,所述昆虫可以为吸血昆虫。
所述方法可以包括使位于所述环境中的宿主表面与所述化合物接触;可以包括以气溶胶或雾气形式传递到所述环境中;可以包括施加到所述环境中的水表面;可以包括施加到所述环境中的遮蔽物或包覆物表面;可以包括在所述环境中使用含有所述化合物的遮蔽物或包覆物物品;或可以包括使所述化合物的固体形式沉积于所述环境中。所述化合物可以是VUAA1。所述方法可以进一步包括向所述环境提供驱虫剂,例如驱蚊剂。
在另一实施方案中,提供一种容器,其包含呈液体或气体分散体形式的VUAA1。气体分散体可以是气溶胶。所述容器可以进一步包含喷嘴或阀门、多孔施加器或滚动施加器。
在又一实施方案中,提供一种织物或材料,其包含VUAA1。所述织物或材料可以是包覆物、遮蔽物、衬垫或网织物。
在又一实施方案中,提供一种水溶性片剂,其包含VUAA1。
其他实施方案包括:
中断蚊媒疾病传播的方法,其包括向蚊虫环境提供结合于和/或促进蚊虫ORco离子通道(例如AgOR7)的化合物;
减少蚊虫叮咬的方法,其包括向蚊虫环境提供结合于和/或促进蚊虫ORco离子通道(例如AgOR7)的化合物;
减少蚊虫繁殖的方法,其包括向蚊虫环境提供结合于和/或促进蚊虫ORco离子通道(例如AgOR7)的化合物;
减少环境中的蚊虫侵扰的方法,其包括向所述环境提供结合于和/或促进蚊虫ORco离子通道(例如AgOR7)的化合物;
减少昆虫群体对作物的损害的方法,其包括向作物生长环境提供结合于和/或促进ORco离子通道的化合物;以及
减少损害作物的昆虫侵扰的方法,其包括向繁殖有损害作物的昆虫群体的作物生长环境提供结合于和/或促进ORco离子通道的化合物。
可预期,本文描述的任何方法或组合物可以相对于本文描述的任何其他方法或组合物来实施。
词“一种(a)”或“一个(an)”的使用当在权利要求书和/或说明书中结合术语“包含(comprising)”使用时可以意指“一个(种)(one)”,但它也与“一个(种)或多个(种)(one ormore)”、“至少一个(种)(at least one)”以及“一个(种)或多于一个(种)(one or morethan one)”的含义一致。
当结合以下描述以及随附图式考虑时,将可更好地认识和理解本发明的这些和其他实施方案。然而,应了解,以下描述尽管指示本发明的各种实施方案和其许多细节详情,但只是作为例证来给出,而不具有限制性。可以在本发明范畴内在不偏离其精神的情况下作出许多替代、修改、添加和/或重置,并且本发明包括所有这些替代、修改、添加和/或重置。
附图说明
以下图式构成本说明书的一部分并且被包括在内以便进一步展示本发明的某些方面。通过参考这些图式中的一个或多个图结合本文呈现的对具体实施方案的详细说明可以更好地理解本发明。
图1.嗅觉的暗示在成年蚊虫中在介导数种关键行为时构成主要的感觉模态。这些行为包括花蜜吸取、选择产卵地点、配偶选择以及尤其是宿主(血液餐)选择性,其中化学和温度输入最为增效。
图2.一般昆虫嗅觉信号转导的规范和非规范模型。图解合并了最近对于昆虫ORN的内腔和树突膜中分子间相互作用的观点。通过表皮孔输入的一般气味负载到OBP上,它们在规范的OR复合物情形下有助于输送到常规的OR(ORx)。气味的输送由特定OBP所引导,它可以以物理方式与常规的和/或Orco家族的OR相互作用。信息素敏感性路径很可能涉及额外的分子组分。在规范模型(I型、II型)中,常规的OR(OrX)结合气味并且以物理方式与高度保守的非常规的Orco家族OR(冈比亚按蚊中的AgO7)相互作用,以形成表达于大多数ORN中的功能性异源多聚体。在这个模型中,气味的结合活化促离子型信号传导路径(Sato等人,2008)并且可能活化促代谢型信号传导路径(Wicher等人,2008)。在其他ORN中,非规范OR(第III型),例如IGluR/IR基因家族成员(Benton等人,2009)对非典型气味起反应,这在有些情况(例如氨和乳酸)下与源自人类的种间激素相关联。
图3A-3F.VUAA1在表达AgORco和其直系同源物的HEK293细胞中激起可见电流。(图3A)VUAA1的结构。(图3B)由对VUAA1起反应的AgORco和AgORco+AgOR10细胞系基于氟代-4乙酰氧基甲酯的Ca2+成像产生的浓度反应曲线(CRC)。(图3C到图3D)关于在稳定地表达单独AgORco和AgORco+AgOR10的细胞中对VUAA1的浓度依赖性反应的全细胞膜片钳记录结果。(图3E)苯甲醛(BA)(一种AgOR10促效剂)针对AgORco+AgOR10细胞引起浓度依赖性反应。(图3F)在表达DmOR83b和HvOR2的HEK293细胞中对VUAA1的全细胞电流反应。在-60mV下钳制图3C、图3D、图3E和图3F的细胞。
图4A-4D.通道样电流由向表达单独AgORco或呈复合物形式的AgORco的细胞施加 VUAA1而产生。(图4A到图4C)在AgORco(图4A)和AgORco+AgOR10(图4B到图4C)细胞中的电压依赖性电流的代表性迹线。保持电位按20mv的增量从-60mV变化到+40mV。(图4D)来自归一化峰电流的(图4A)n=3、(图4B)n=7和(图4C)n=4的电流-电压关系。
图5A-5D.AgORco是一种功能性通道并且在膜外面向外的膜片中对VUAA1起反应。(图5A)来自从表达AgORco7的HEK293细胞拉出的外面向外切取的膜片的单通道记录。(图5B到图5D)迹线(图5A)在施加-4.0logM VUAA1持续5秒之前(图5B)、期间(图5C)以及之后(图5D)的扩展。在图5B到图5D中插入迹线扩展的所有点电流直方图。使切取的膜片保持在-60mV下。
图6A-6D.VUAA1活化雌性冈比亚按蚊中表达AgORco的神经元。(图6A)在电极刺穿下来自头状突起感觉器(capitate peg sensilla)的SSR记录的代表性迹线。通过玻璃记录电极传递VUAA1或单独传递媒剂(DMSO)。可由较小CpB/C动作电位辨别出CpA。将制备物保持在稳定又湿润的合成空气流(21%O2/79%N2)以限制CpA的基本活性。(图6B)如图3A中的迹线的扩展。(图6C)对VUAA1起反应的CpA神经元的活性。在感觉器刺穿之后最初10秒内按每一秒并且在此之后每10秒计算峰频率(Spike frequency)。在60秒之后,用大气空气对制备物进行脉冲调制持续2秒以确认功能性CpA神经元。分析中不包括对CO2或1-辛烯-3-醇不起反应的感觉器。(图6D)如图6C中对VUAA1起反应的CpB/CpC神经元的活性。
图7A-7F.VUAA1和BA反应是OR特异性的。(图7A)来自图7C到图7E中的浓度依赖性反应的归一化电流的直方图(n=5).(图7B)未转染的HEK293细胞不对VUAA1或者BA起反应(n=5)。(图7C)将GFP与DmOR83b或HvOR2共转染以鉴别表达OR的细胞。单独GFP的细胞不具有来自VUAA1或BA的电流(n=4)。(图7D到图7E)为了比较,AgORco和AgORco+AgOR10细胞均在VUAA1施加期间去极化,而仅AgORco+AgOR10细胞对BA起反应。所有记录的保持电位为-60mV。(图7F)VUAA1不会在稳定地表达另一阳离子通道大鼠瞬时受体电位香草酸1(rTRPVl)的细胞中激起电流,但对促效剂辣椒素起反应。
图8A-8D.8-Br-cAMP和8-Br-cGMP不会在AgORco或AgORco+AgOR10细胞中激起电 流。(图8A)在施加8-Br-cAMP、8-Br-cGMP和BA下来自表达AgORco+AgOR10的细胞的全细胞记录的代表性迹线(n=4)。(图8B)在施加8-Br-cAMP、8-Br-cGMP和VUAA1下来自AgORco细胞的代表性迹线(n=4)。所有记录的保持电位为-60mV。(图8C)在施加8-Br-cGMP下来自表达rCNGA2的细胞的代表性迹线。所有记录的保持电位为-60mV。(图8D)来自环核苷酸和对照反应的归一化电流的直方图(n=5)。
图9.VUAA1的幼虫活性临限值相对于DEET低5个数量级并且为AgORco依赖性的。使用Ethovision(Noldus)软件在6孔培养板中经5分钟监测冈比亚按蚊中的幼虫活性。对VUAA1的幼虫反应(左起第三到第八)显著高于对DEET的那些反应(左起第九到第十一)。基因沉默研究(左起第十二到第十四)证明对VUAA1的幼虫反应与VUAAl作用模式一致,为AgORco依赖性的。
具体实施方式
优选实施方案的详细说明
昆虫通过使用一系列细胞表面嗅觉受体(OR)来感觉称为气味的挥发性化学物来理解其化学环境。为了接收气味,必须存在OR的ORco家族中的一员以便偶合于另一截然不同的负责感觉不同气味的OR(ORX)。每个昆虫物种具有许多Or,它们一般具有物种特异性,但仅一个Orco家族成员在所有昆虫类群中极其保守。迄今为止尚未报导有ORco配体。作为一项旨在鉴别调节OR活性的化合物的高产量筛选的一部分,本发明者发现了第一个ORco家族活化剂。这种ORco家族活化剂,被称为VUAA1,理论上能够活化所有ORX/ORco复合物。食血昆虫寻找宿主的行为主要是由它们的嗅觉驱动的。这种食血行为成为它们传播疾病的能力的基础。通过直接化学干扰,例如由VUAA1干扰来破坏嗅觉介导的行为的能力将会在对抗媒介传播疾病中成为一个很大的进步,并且调节ORco复合物将会使昆虫不能表现其通常的行为,例如寻找宿主和吸取花蜜。VUAA1还可以用于破坏每年在全世界范围内导致数亿美元的作物损害的农业上重要的昆虫害虫的行为。
I.蚊虫
蚊虫(Mosquito),来自西班牙语或葡萄牙语,意指“小飞虫”,是一种普通的属于蚊科(Culicidae)的昆虫。蚊虫类似于大蚊(大蚊科(Tipulidae))和摇蚊(摇蚊科(Chironomidae)),对此,它们有时会让外行的观察者感到混淆不清。
蚊虫在它们的生命周期中经历四个阶段:卵、幼虫、蛹和成虫或蛾。雌性成虫在可以是盐沼、湖泊、水坑、植物上的天然储库或人造水容器(例如塑料桶)中的水中产下它们的卵。前三个阶段在水中发生并且持续5到14天,视物种和周围温度而定;卵孵化,变成幼虫,然后成蛹。当蛹漂浮在水表面上时由蛹孵出成年蚊虫。成虫可以活4至8周。
雌性蚊虫具有适合于刺入植物和动物表皮的口器。尽管雄虫通常以花蜜和植物汁为食,但雌虫在它可以产卵之前需要从“血液餐”获得营养。
蚊虫幼虫具有发育良好的带有用来采食的口刷的头部、没有足部的大胸部以及分节腹部。幼虫通过位于第八腹节上的呼吸孔,或通过管状口器呼吸,并且因此必须经常地浮出表面。幼虫花费大部分时间用来摄取微表层中的藻类、细菌和其他微生物。它们只有当受干扰时才会潜到表面以下。幼虫通过口刷的推进力,或者通过整个肢体的抖动来游泳。幼虫发育要经历四个阶段或龄期,在此之后它们变成蛹。在每个龄期结束时,幼虫脱皮,脱落它们的甲壳或表皮,以便为进一步生长作准备。成虫的长度有所不同,但很少超过16mm(0.6英寸),并且重量达2.5mg(0.04格令)。所有蚊虫具有细长的躯体,分三节:头部、胸部以及腹部。
蛹呈逗点状,如同在按蚊中当从侧面观察时所见。头部和胸部合并成头胸部,腹部环绕在其下面。如同幼虫一样,蛹必须经常地浮出表面以进行呼吸,对于这,它们是通过头胸部上的一对呼吸角来进行。然而,蛹在这个阶段不摄食。几天以后,头胸部的背面分裂并且成年蚊虫显露出来。蛹不如幼虫活跃。
从卵到成虫的持续时间在物种之间有所不同并且很受周围温度的影响。蚊虫能够在只不过5天内从卵发育成成虫,但在热带环境下通常要花费10至14天。成年蚊虫躯体大小的变化取决于繁殖水内的幼虫群体密度和食物供应。飞蚊成虫经常地栖息在它们在草根正下方建立的通道中。
成年蚊虫通常在从蛹期显露出来之后数天以内交配。在大多数物种中,雄虫形成几大群,通常大约在黄昏时分,并且雌虫飞入这些群体中进行交配。
雄虫能活约一周时间,以花蜜和其他糖源为食。雌虫也将会以糖源为食来补充能量,但通常为了卵的发育而需要血液餐。在获得充足的血液餐之后,雌虫将会在消化血液并且卵进行发育时休息几天。此过程取决于温度,但在热带环境下通常要花费2至3天。一旦卵完全发育,雌虫就产下它们并且重新开始寻找宿主。周期自身不断地重复直到雌虫死亡。它们的寿命取决于温度、湿度以及它们在避免宿主防御时成功地获得血液餐的能力。
头部专门是用于获取感觉信息和用于摄食。头部含有眼睛和一对长长的分多节的触须。触须对于探测宿主气味以及雌虫产卵所处的繁殖位置的气味很重要。在所有蚊虫物种中,相较于雌虫,雄虫的触须明显浓密并且含有听觉受体,它们用来探测雌虫特有的呜鸣声。复眼明显地彼此隔开。它们的幼虫仅仅具有凹眼眼点(pit-eye ocellus)。成虫的复眼在头部的一个单独区域内显现。新的小眼呈半圆形成排地附连在眼睛后面;在生长的第一个阶段期间,这导致个别的小眼是正方形,但后来在发育中,它们变为六角形。六角形模式将仅在具有正方形眼睛的阶段中的甲壳脱落时才会变得可见。头部还具有一个用来摄食的细长形向前突出的“刺状”喙部以及两个感觉触须。雄虫的下颚须比它们的喙部长,而雌虫的下颚须则短得多。如同蚊虫家族的许多成员一样,雌虫具备有细长形喙部,它将其用来收集血液以便为它的卵提供养分。
胸部专门是用于移动。胸部附接有三对足和一对翅。昆虫翅膀是甲壳的长出物。按蚊可以在夜间按1到2公里/小时(0.62到1.2英里/小时)连续地飞翔达到4小时,行进达到12千米(7.5英里)的距离。
腹部专门是用于消化食物和使卵发育。这个分节躯体部分在雌虫吸取血液餐时显著膨胀。随时间消化血液,从而充当蛋白质来源来用于产卵,这些卵逐渐地填充腹部。
从卵到成虫的持续时间在物种之间有所不同并且很受周围温度的影响。蚊虫能够在只不过5天内从卵发育成成虫,但在热带环境下通常要花费10至14天。成年蚊虫躯体大小的变化取决于繁殖水内的幼虫群体密度和食物供应。飞蚊成虫经常地栖息在它们在草根正下方建立的通道中。
成年蚊虫通常在从蛹期显露出来之后数天以内交配。在大多数物种中,雄虫形成几大群,通常大约在黄昏时分,并且雌虫飞入这些群体中进行交配。雄虫能活约一周时间,以花蜜和其他糖源为食。雌虫也将会以糖源为食来补充能量,但通常为了卵的发育而需要血液餐。在获得充足的血液餐之后,雌虫将会在消化血液并且卵进行发育时休息几天。此过程取决于温度,但在热带环境下通常要花费2至3天。一旦卵完全发育,雌虫就产下它们并且重新开始寻找宿主。周期自身不断地重复直到雌虫死亡。它们的寿命取决于温度、湿度以及它们在避免宿主防御时成功地获得血液餐的能力。
为了使蚊虫获得血液餐,它必须避开脊椎动物的生理学反应。蚊虫,如同所有食血节肢动物一样,具有有效地以它们的唾液阻止止血系统的机制,所述唾液含有一种分泌蛋白质混合物。蚊虫唾液会负面地影响着血管收缩、血液凝固、血小板凝聚、血管生成以及免疫性并且引起发炎。普遍来讲,食血的节肢动物唾液含有至少一种抗凝血剂、一种抗血小板剂以及一种血管舒张物质。蚊虫唾液还含有有助于摄取糖的酶和用于控制糖餐中的细菌生长的抗微生物剂。蚊虫唾液的组成相对简单,因为它通常含少于20个占优势的蛋白质。尽管最近对于这些分子和它们在食血中的作用的认识取得了很大进步,但科学家们仍然不能把功能归结于节肢动物唾液中所发现的大半分子。一种有前景的应用是基于唾液分子开发抗凝血药物,所述药物可能适用于解决心脏相关疾病,因为它们是使用方便的凝血抑制剂和毛细管扩张剂。
在雌性蚊虫的生命中两个重要的事件是卵发育和血液消化。在吸取血液餐之后,雌虫的中肠合成了蛋白水解酶,这些酶使血液蛋白质水解成游离氨基酸。这些被用作构建嵌段来合成蛋黄蛋白质。
II.蚊虫传播疾病
蚊虫是在人与人之间传播致病性病毒和寄生虫但本身未感染疾病的媒介因子。主要的蚊虫传播疾病是病毒疾病:黄热病(yellow fever)、登革热(dengue fever)和切昆贡亚热(Chikungunya),多半是通过埃及伊蚊(Aedes aegypti)传输;以及疟疾,通过按蚊属虫传播。尽管最初引起公共卫生的关注,但HIV现被认为几乎不可能由蚊虫来进行传输。
据估计,蚊虫在非洲、南美洲、中美洲、墨西哥以及大部分亚洲地区每年向超过7亿人传输疾病,并且有数百万人因此死亡。每年至少2百万人死于这些疾病。
用于防止传播疾病或用于保护疾病流行区域的个体的方法包括旨在蚊虫根除的病媒控制、疾病预防、使用预防性药物和开发疫苗以及用杀昆虫剂、网具和驱避剂防止蚊虫叮咬。因为大多数这样的疾病是由较老的雌虫所传播的,所以科学家们提议聚焦于这些雌虫来避免演变出抗性。
A.原生虫
按蚊属蚊属携带疟疾寄生虫(参见疟原虫(Plasmodium))。在全世界范围内,疟疾是过早死亡的一大主要原因,在不到5岁的儿童中尤为如此。它在热带和亚热带区域,包括美洲部分区域(22个国家)、亚洲和非洲广泛流行。每年,大约有350到500百万例的疟疾,致使1百万到3百万人死亡,其中大多数是撒哈拉以南非洲地区的幼小儿童。百分之九十的疟疾相关性死亡是在撒哈拉以南的非洲发生。疟疾通常与贫穷有关,并且可能实际上是贫穷的一个原因和经济发展的一大障碍。
5种疟原虫寄生虫可能会感染人类;最严重形式的疾病是由恶性疟原虫(Plasmodium falciparum)引起。由间日疟原虫(Plasmodium vivax)、卵形疟原虫(Plasmodium ovale)和三日疟原虫(Plasmodium malariae)所引起的疟疾在人类中引起较轻的疾病,也就是说一般不致命。第五种诺氏疟原虫(Plasmodium knowlesi)引起一种人畜共患病(zoonosis),它在猕猴中导致疟疾,但还可以感染人类。
疟疾是自然地通过雌性按蚊属蚊虫的叮咬来传输。当蚊虫叮咬受感染者时,吸取少量血液,所述血液含有疟疾寄生虫。这些寄生虫在蚊虫体内发育,并且在约一周后,当蚊虫吸取它的下一顿血液餐时,寄生虫通过蚊虫唾液被注入到所叮咬的人体内。在肝脏中经过介于两周与数月(有时数年)之间的一段时间之后,疟疾寄生虫开始在红血细胞内部敏殖,从而引起包括发烧和头痛的症状。在严重情况下,疾病恶化,导致幻觉、昏迷和死亡。
多种抗疟疾药物可以用来治疗疟疾。在最近5年里,在疾病流行国家中恶性疟原虫感染的治疗已经通过使用含有青蒿素(artemisinin)衍生物的药物组合而发生转变。严重的疟疾是用静脉内或肌肉内注射的奎宁,或者越不越多地用青蒿素(artemisinin)衍生物青蒿琥酯(artesunate)来治疗的。数种药物还可以用来在到达疟疾流行国家的旅行者中防患疟疾(预防)。已经对数种抗疟疾药物,最显著的是氯喹显现出抗性。
疟疾传输可以通过经由布置便宜的蚊虫网具和驱虫剂来防止蚊虫叮咬,或者通过蚊虫控制措施,例如在蚊虫产下它们的卵所处的住宅和排放滞水内喷洒杀昆虫剂而减少。尽管有许多方法处于开发阶段,但制造广泛可用并且能在持续时间内提供高保护水平的疫苗的挑战仍有待满足。
B.蠕虫病
一些种类的蚊虫会携带丝虫病蠕虫,这种寄生虫会引起损伤外貌的病状(常常称为象皮病),其特征为身体的数个部分有很大肿胀;在全世界范围内,约4千万人带有丝虫病残疾而活着。线状丝虫线虫(蛔虫)是丝虫总科(superfamily Filarioidea),也称为“丝虫属(filariae)”的成员。已知有9种丝虫线虫使用人类作为终宿生(definitive host)。这些线虫根据在身体内部它们所占据的生态位(niche)而分属3个群组:淋巴丝虫病、皮下丝虫病和浆膜腔丝虫病。淋巴丝虫病是由蠕虫班氏丝虫(Wuchereria bancrofti)、马来丝虫(Brugia malayi)和帝纹丝虫(Brugia timori)引起。这些蠕虫占据淋巴系统,包括淋巴结,并且在慢性病例中,这些蠕虫导致疾病象皮病。皮下丝虫病是由罗阿丝虫(非洲眼睛蠕虫)、链尾丝虫(mansonella streptocerca)、盘尾丝虫(Onchocerca volvulus)和麦地那虫(Dracunculus medinensis)(几内亚丝虫)引起。这些蠕虫占据脂肪层中皮肤的皮下层。浆膜腔丝虫病是由蠕虫常现曼森线虫(Mansonella perstans)和奥氏曼森线虫(Mansonellaozzardi)引起,这些蠕虫占据腹部的浆膜腔。在所有情况下,传输媒介物是吸血昆虫(飞蝇或蚊虫),抑或在麦地那虫情况下是挠足型甲壳类虫。
因丝虫蠕虫受感染的个体可以被描述为“微丝蚴血症型(microfilaraemic)”或者“无微丝蚴血症型(amicrofilaraemic)”,这取决于是否会在它们的周边血液中发现微丝蚴(microfilaria)。在微丝蚴血症病例主要通过直接观测周边血液中的微丝蚴来诊断丝虫病。在无微丝蚴血症病例中基于临床观察并且有时通过在血液中发现循环抗原来诊断隐性丝虫病。
C.病毒
病毒疾病黄热病是一种急性出血性疾病,多数是通过埃及伊蚊蚊虫传输的。其病毒是一种具有黄病毒科(Flaviviridae family)的正义的40到50nm包膜RNA病毒。黄热病病毒是通过雌性蚊虫(黄热病蚊虫埃及伊蚊和其他种类)的叮咬传输的,并且发现于南美洲和非洲的热带和亚热带区域,而不是在亚洲。所述病毒仅有的已知宿主是灵长目动物和数种蚊虫。所述疾病的起源很可能是非洲,由此处它通过16世纪的奴隶贸易而被引入南美洲。从17世纪以来,已经在美洲、非洲和欧洲记录有所述疾病的数桩重大流行病事件。在19世纪,黄热病被认为是最危险的传染病之一。
在临床上,黄热病在大多数病例中呈现有发烧、恶心和疼痛,并且它一般在数天之后消退。在一些患者中,紧跟着是毒性期,其中会出现伴有黄疸的肝脏损害(赋予疾病名称)并且导致死亡。因为出血倾向增大(出血素质),因此黄热病属于出血热群组。WHO估计,黄热病每年在未接种疫苗的群体中引起200,000例疾患和30,000例死亡;在非洲存在约90%的感染率。
从20世纪中期以来,就已经存在一种针对黄热病安全又有效的疫苗并且一些国家要求旅行者接种疫苗。因为没有疗法已知,因此接种疫苗计划与旨在减少传输性蚊虫群体的措施一起在受影响区域极为重要。从1980年代以来,黄热病病例数目正在增加,使它成为再度出现的疾病。
登革热和登革出血热(DHF)是也通过埃及伊蚊蚊虫传输的急性热病。这些出现于热带,可能会危及生命,并且是由黄病毒科黄病毒属(genus Flavivirus)的4种密切相关的病毒血清型引起。因为它可能极其痛苦,因此它又被称为断骨热(breakbone fever)。它广泛地出现在热带,并且越不越多地出现在中国南方。不同于疟疾,登革热在市区的流行范围与它在农村地区的流行范围一样。每个血清型十分不同以至于不存在交互保护并且可能会出现由多个血清型(超地方流行性(hyperendemicity))所引起的流行病。登革热是通过埃及伊蚊(Aedes aegypti)(覆蚊亚属(Stegomyia))或者很少是通过白纹伊蚊(Aedesalbopictus)蚊虫被传输给人类的。传播登革热的蚊虫通常在黄昏和黎明时分进行叮咬,但也会在日间任何时候,尤其在室内,在有遮荫的区域,或者当天气多云时进行叮咬。WHO称大约有25亿人,即全世界人口的五分之二正处于登革热的风险之中,并且估计,在全世界范围内每年可能有五千万登革热感染病例。这种疾病现在在超过100个国家里流行。
其他如流行性多关节炎、裂谷热(Rift Valley fever)、罗斯河热(Ross RiverFever)、圣路易脑炎(St.Louis encephalitis)、西尼罗河病毒(West Nile virus,WNV)、日本脑炎(Japanese encephalitis)、拉克罗斯脑炎(La Crosse encephalitis)以及数种其他脑炎型疾病的病毒疾病是通过数种不同的蚊虫传播的。东方型马脑炎(Eastern equineencephalitis,EEE)和西部马脑炎(Western equine encephalitis,WEE)出现于美国,在此处它在人类、马类和一些禽类中引起疾病。因为死亡率高,因此EEE和WEE在美国被认为是两种最严重的蚊虫传播疾病。症状从轻度流感样疾病变化到脑炎、昏迷和死亡。库蚊属(Culex)和脉毛蚊属(Culiseta)也被涉及于传输所述疾病。WNV最近在美国受到关注,从而促成积极的蚊虫控制计划。
D.传播
蚊虫的摄食时间常常不会被察觉;叮咬仅仅因为它引起免疫反应才变得明显。当蚊虫叮咬人类时,它注入唾液和抗凝血剂。对于任何既定个体,在最初叮咬下没有反应,但在随后的叮咬下,身体免疫系统显现抗体并且叮咬处在24小时内变得红肿和发痒。这是幼小儿童中的通常反应。随着有更多叮咬,人类免疫系统的敏感性增加,并且在数分钟内出现发痒的红色蜂巢状团块,在此处免疫反应使微血管断开并且流体聚集在皮肤以下。这类反应在大龄儿童和成人中是常见的。一些成人可能会对蚊虫变得不敏感并且对它们的叮咬几乎没有反应,而其他人可能会对叮咬变得高度敏感,引起水疱、抓伤和大的炎症反应,即一种被称为蚊咬综合征(Skeeter Syndrome)的反应。
III.昆虫嗅觉受体
察觉化学环境和对化学环境作出反应的能力是吸血的(食血)昆虫的许多基本行为中关键性的感觉输入(Zwiebel和Takken,2004;图1)。寻找脊椎动物的血液餐通常涉及一段距离的飞行以便到达宿主。这种行为由一系列行为阶段组成,开始于由宿主化学气味(种间激素)激活感受性昆虫并且当昆虫停落于宿主上时结束(Takken,1991)。在很近的范围里,吸引力是通过数种有气味的物质来介导,其中之一是CO2。与其他源自宿主的有机化学物结合,CO2充当增效剂,因为它大大地增强了由其他挥发物触发的吸引力(Gilles,1980)。此外,似乎是蚊虫对CO2的浓度变化,而不是它的存在与否作出反应。在埃及伊蚊中,浓度增加只不过0.01%即能观察到CO2受体触发率的变化(Kellogg,1970),但在增加0.03%到0.05%之后观察到行为变化(Eiras和Jepson,1991)。此外,对CO2作用细心的检验显示在实验室中气味流的紊乱大大地影响了埃及伊蚊和冈比亚按蚊的反应性(Dekker等人,2001a)。
冈比亚按蚊也已显示会受丙酮、乳酸(Acree等人,1968)、羧酸类(Meijerink和vanLoon,1999)、氨、4-甲基苯酚、1-辛烯-3-醇和汗液中的其他组分(Cork and Park,1996;Meijerink等人,2001)以及人类足部的气味、呼气和林堡干酪的数种未鉴别的组分吸引(DeJong和Knols,1995)。此外,在人类对于蚊虫来说的吸引力中常常提到的差异(Curtis,1986)几乎肯定是以嗅觉为基础的(Qiu等人,2006a;Schreck等人,1990)。这种宿主内有差异的行为最尤其是表现在好吸人血的蚊科蚊虫中,例如埃及伊蚊和冈比亚按蚊(de Jong和Knols,1995;Lindsay等人,1993;Schreck等人,1990)。宿主年龄而不是性别可能会影响这些个体间的差异(Carnevale等人,1978);而种族也看来似乎没有影响(Schreck等人,1990)。幼小儿童已显示对于按蚊来说的吸引力不如成人(Muirhead-Thomson,1951;Thomas,1951)。对于人类挥发物的化学组成的研究(Bernier等人,1999;Krotoszynski等人,1977;Labows,1979)显示存在大量(>350)化学物,并且研究正在进行之中以便调查调节蚊虫行为的这些挥发物中最重要的组分。最后,同样很显然的是,对于CO2的反应影响着在吸引力方面个体间的差异(Brady等人,1997),并且因此,CO2可充当许多蚊虫种类的一种通用引诱剂(Gillies,1980;Takken等人,1997;Takken和Knols,1999)。已有报导称CO2刺激因宿主体味而加强,并且对寻找宿主的按蚊具有激活效应,从而促成起飞和持续飞行的行为(Dekker等人,2001b;Gillies,1980;Mboera和Takken,1997)。
在类似于人类以及其他昆虫中的嗅觉的过程中,通过化学感受性信号转导的过程引起蚊虫嗅觉,由此化学信号(通常为环境暗示(environmental cue))被转变成神经元活动,并且最终转变成行为输出。在冈比亚按蚊中,这发生在专门的称为感觉器的毛发样结构内,所述感觉器分散在成虫和幼虫期按蚊的触须和其他头部附体各处(Zwiebel和Takken,2004;图2)。
直到最近,许多发明者有关昆虫嗅觉信号转导在分子水平上的观点已受到在脊椎动物、甲壳类动物和线虫中所获得的观测结果的很大影响(Hildebrand和Shepherd,1997;Krieger和Breer,1999)。规范模型涉及七螺旋G蛋白偶合受体(GPCR)家族,这些受体通过异源三聚的GTP结合(G)蛋白和传统的第二信使而活化下游效应子。尽管没有完全被接受(参见下文),但是长久以来假定,嗅觉信号转导的规范模型在昆虫中将会同样适用,其中已经鉴别了数种“普通的”分子疑似物,并且部分已得以在功能上加以表征。这些包括抑制蛋白类(arrestins)(Merrill等人,2002;2003;2005)、气味结合蛋白(OBP)(Pelosi和Maida,1995)、异源三聚的G蛋白(Laue等人,1997)以及CNG(Baumann等人,1994;Krieger等人,1999)和IP3门控型离子通道(Stengl,1994)。在使用蟑螂的一项研究中,已证实,昆虫触角标本暴露于信息素会引起IP3水平的快速增加(Breer等人,1990),这在追踪研究中能够用百日咳毒素抑制(Boekhoff等人,1990),这表明IP3增加取决于Gai或Gao G蛋白亚单位。近年来,本发明者进行了一项有关G蛋白在冈比亚按蚊嗅觉附体中的表达的分子调查,其中沿着多数嗅觉感觉神经元的树突观察到与涉及到嗅觉信号转导中一致的Gaq定位(Rutzler等人,2006)。此外,家蚕(Bombyx mori)的信息素受体神经元活动能够用氟离子刺激(Laue等人,1997),已知这些氟离子能通过与镁离子化合而结合于亚单位来活化异源三聚的G蛋白(Antonny等人,1993)。然而,尽管有这种正在不断增长的丰富信息,但昆虫嗅觉信号转导的确切模式仍然甚是模糊,并且因此成为正在进行中的研究的主题,它关于基于GPCR的模式的有效性已经引起了一些严重的问题。
因为嗅觉在脊椎动物和至少一种无脊椎动物中均是GPCR来介导的,因此可假定,昆虫同样将会在嗅觉信号转导中利用这些蛋白质。实际上,已经使用多种途径在黑腹果蝇中鉴别出一大家族的候选OR(Clyne等人,1999)(Gao和Chess,1999;Vosshall等人,1999)。在这些研究的第一项研究中,使用一种能搜索为已知横跨膜蛋白质所共有的保守性物理化学特征的新颖计算机算法(Kim等人,2000)而不是依赖于基于序列同源性的筛选(它可能会遗漏特定家族中的一个不同的成员)来鉴别出推定的黑腹果蝇Or(Dor)。最终使用这些策略鉴别的结构导致鉴别一个高度不同的受体家族,展现介于10%与75%之间的一致性并且与任何其他GPCR家族不具有显著的同源性(Smith,1999)。也在黑腹果蝇和冈比亚按蚊中描述了另一个化学感受性受体家族并且推测其包含味觉(味道)受体(Clyne等人,2000;Hill等人,2002;Scott等人,2001)。推断嗅觉功能的另一个间接准则已经由各种原位表达模式研究提供,这些研究已经证明大多数这些基因有选择地并以常规方式表达在飞虫嗅觉感觉神经元中(Clyne等人,1999)(Elmore和Smith,2001;Gao和Chess,1999;Vosshall,2001;Vosshall等人,1999)。双色(双重标签)原位杂交表明,在两个显著的警示下(Goldman等人,2005),多数黑腹果蝇ORN很可能表达单个DOR基因(Vosshall等人,2000),这类似于哺乳动物系统(Mombaerts,1999),但与秀丽隐杆线虫(C.elegans)系统完全不同。对于一个ORN-一个受体的原则来讲,非常规的DOR83b明显是一个例外,它现在被称为DmORco。不同于多数其他DOR,DmORco表达于黑腹果蝇的大多数触角和下颚须ORN中。已经在广泛范围的昆虫种类中鉴别出推定的DmORco直系同源物并且这些直系同源物具有许多特征,包括高序列一致性(Pitts等人,2004)、特有的广泛表达模式(Krieger等人,2003)和保守功能(Jones等人,2005)。ORco家族成员被认为是非常规的OR,因为它们充当DOR家族的其他成员的一般二聚搭配物(Larsson等人,2004)。近年来,Benton、Vosshall和同事已经鉴别了一组新型的促离子型谷氨酸受体,其作为一类新的昆虫化学感受性受体(IR)表达于与腔锥感觉器(coeloconic sensilla)相关的DmOrco-ORN中,在所述腔锥感觉器处它们与“传统的”昆虫OR相同地起作用以对氨和其他环境暗示作出反应(Benton等人,2009;Liu等人,2010)。
Vosshall实验室精确的研究也表明了相对于脊椎动物OR,昆虫OR显现一种新颖的拓扑结构(Benton等人,2006)。在缺乏实际结构信息的情况下,多半是基于源自脊椎动物的生物信息模型来对昆虫OR进行结构表征(Clyne等人,2000;Vosshall等人,1999)。实际上,尽管基于序列的种系发生认为昆虫OR一般包含独特的七螺旋受体家族并且这些受体是由原始的化学感受性受体扩展而来的系列(Mombaerts,1999;Robertson等人,2003),但是正在不断地认识到,昆虫OR很可能是一组结构上独特的感觉蛋白质。这些研究提供有力的证据来支持以下观点:果蝇属OR为介于非常规的DmORco与常规的气味结合DOR之间呈现新颖的膜拓扑结构的异聚复合物,在这个拓扑结构中,N末端在细胞内,而不是脊椎动物OR和GPCR所特有的细胞外定位(Benton等人,2006)。独立的验证(Lundin等人,2007)连同最近采用“强烈反对”将节肢动物OR归类为GPCR的隐马尔可夫建模(hidden Markov modeling)进行的计算分析(Wistrand等人,2006)引起了关于在昆虫中气味活化下游端的信号传导路径性质的重大关注。实际上,最近的两项研究提供了有争议的证据来提出果蝇属OR显现了配体门控型离子通道(Sato等人,2008)和环状核苷酸门控型离子通道(Wicher等人,2008)两者的性质。尽管这些假设在它们的详细细节上仍然有所不同,但正在不断地认识到,昆虫嗅觉转导可能不同于脊椎动物的模式并且充当非GPCR介导型离子通道(图2)。在任何情况下,尽管当前的假设可能不同,但是关于昆虫嗅觉转导可能不同于脊椎动物的模式并且经由例如离子通道的非GPCR介导型机制来起作用不断增长的可能性(图2)却很有说服力。
在有关除了昆虫模型系统黑腹果蝇以外的昆虫OR的首次报导中,发明者实验室成员作为与Drs.John Carlson和Hugh Robertson合作努力的一部分负责鉴别有选择地表达于冈比亚按蚊的嗅觉组织中的一组候选Or基因(AgOR)(Fox等人,2001)。此外,所述报导也证实,最初的这组AgOR中至少有一个展现雌性特异性表达,这是可能尤其与疾病传输相关的特征。在随后的一项研究中,作为旨在注释最近完善的冈比亚按蚊基因组序列的努力(Holt等人,2002)的一部分,本发明者(同其他团体合作)利用生物信息和分子途径来描述整个冈比亚按蚊GPCR基因家族(AgGPCR);在275个推定AgGPCR中,描述了79个候选AgOR(Hill等人,2002)。此外,已经使用一种类似的生物信息途径(使用非公开的数据库)来鉴别实夜蛾属蛾虫烟芽夜蛾(Heliothis virescens)中的九个候选Or基因(Krieger等人,2002),其中一些与AgOr具有序列同源性。最近,已经在蜜蜂意大利蜂(Apis mellifera)(Robertson和Wanner,2006)、埃及伊蚊(Bohbot等人,2007)和赤拟谷盗(red flourbeetle,Tribolium casteneum)(Engsontia等人,2008)的基因组序列中鉴别出一大家族的候选Or基因。
迄今为止,昆虫OR已经在许多异源系统中得以广泛地去孤儿化(deorphanized)。有关昆虫OR首次获得成功的功能研究是针对DOR43a使用非洲爪蟾属(Xenopus)卵母细胞表达系统(Wetzel等人,2001)来进行,并且在黑腹果蝇中的过度表达(Storkuhl和Kettler,2001)显示对一组4个的气味的敏感度增加。卡尔森(Carlson)实验室使用了一种新颖的实验途径,其利用黑腹果蝇的一个遗传品系,其中染色体缺失已导致ab3A ORN失去内源受体(DOR22a/b)。因此形成的“空神经元(empty neuron)”系统有助于使外源OR基因特异性靶向空神经元中,从而允许对新颖受体在用一组不同的气味刺激之后在ab3A神经元内进行化学感受性信号转导的能力进行电生理学评估(Dobritsa等人,2003)已经有效地使用这种系统来对几乎所有的DOR进行功能表征(Hallem等人,2004a)(Hallem和Carlson,2006),从而产生DOR的高度发达的多维“气味空间”图。作为卡尔森实验室与本发明者之间长期存在的合作的一部分,也在果蝇属空神经元中对多个AgOR进行了功能表征(Hallem等人,2004b;Lu等人,2007)。这些研究连同在非洲爪蟾属和细胞培养系统中功能上表达超过40种AgOR方面的成功已经引起在理解嗅觉敏感性在冈比亚按蚊幼虫(Xia等人,2008)和成虫(Lu等人,2007)中的分子基础上取得了重大进展。例如,充当许多种蚊虫的通用引诱剂的CO2(Takken和Knols,1999)在果蝇属中引起避开,其中它已经鉴别为能靶向离散的一群感觉神经元的“应激气味”的活性组分(Suh等人,2007),并且一对高度保守的推定味觉受体(Gr21a和Gr63a)已经显示两者对于介导果蝇属中对CO2的嗅觉敏感性来说均为必需和足够的(Jones等人,2007;Kwon等人,2007)。作为有关冈比亚按蚊下颚须上的嗅觉过程的综合研究的一部分,本发明者已经鉴别了三个Gr21a/63a同系物(AgGr22到24),因为分子搭配物要求同时包含按蚊CO2受体(Lu等人,2007)。
IV.活性剂
根据本发明,提供一种如下所示并且始终被指定为VUAA1的药剂:
这种化合物是通过实施例中所述的筛选程序来鉴别。
也可预期的是活性剂的浓度可以变化。在非限制性实施方案中,例如,组合物可以在其最终形式中包括例如至少约0.0001%、0.0002%、0.0003%、0.0004%、0.0005%、0.0006%、0.0007%、0.0008%、0.0009%、0.0010%、0.0011%、0.0012%、0.0013%、0.0014%、0.0015%、0.0016%、0.0017%、0.0018%、0.0019%、0.0020%、0.0021%、0.0022%、0.0023%、0.0024%、0.0025%、0.0026%、0.0027%、0.0028%、0.0029%、0.0030%、0.0031%、0.0032%、0.0033%、0.0034%、0.0035%、0.0036%、0.0037%、0.0038%、0.0039%、0.0040%、0.0041%、0.0042%、0.0043%、0.0044%、0.0045%、0.0046%、0.0047%、0.0048%、0.0049%、0.0050%、0.0051%、0.0052%、0.0053%、0.0054%、0.0055%、0.0056%、0.0057%、0.0058%、0.0059%、0.0060%、0.0061%、0.0062%、0.0063%、0.0064%、0.0065%、0.0066%、0.0067%、0.0068%、0.0069%、0.0070%、0.0071%、0.0072%、0.0073%、0.0074%、0.0075%、0.0076%、0.0077%、0.0078%、0.0079%、0.0080%、0.0081%、0.0082%、0.0083%、0.0084%、0.0085%、0.0086%、0.0087%、0.0088%、0.0089%、0.0090%、0.0091%、0.0092%、0.0093%、0.0094%、0.0095%、0.0096%、0.0097%、0.0098%、0.0099%、0.0100%、0.0200%、0.0250%、0.0275%、0.0300%、0.0325%、0.0350%、0.0375%、0.0400%、0.0425%、0.0450%、0.0475%、0.0500%、0.0525%、0.0550%、0.0575%、0.0600%、0.0625%、0.0650%、0.0675%、0.0700%、0.0725%、0.0750%、0.0775%、0800%、0.0825%、0.0850%、0.0875%、0.0900%、0.0925%、0.0950%、0.0975%、0.1000%、0.1250%、0.1500%、0.1750%、0.2000%、0.2250%、0.2500%、0.2750%、0.3000%、0.3250%、0.3500%、0.3750%、0.4000%、0.4250%、0.4500%、0.4750%、0.5000%、0.5250%、0.0550%、0.5750%、0.6000%、0.6250%、0.6500%、0.6750%、0.7000%、0.7250%、0.7500%、0.7750%、0.8000%、0.8250%、0.8500%、0.8750%、0.9000%、0.9250%、0.9500%、0.9750%、1.0%、1.1%、1.2%、1.3%、1.4%、1.5%、1.6%、1.7%、1.8%、1.9%、2.0%、2.1%、2.2%、2.3%、2.4%、2.5%、2.6%、2.7%、2.8%、2.9%、3.0%、3.1%、3.2%、3.3%、3.4%、3.5%、3.6%、3.7%、3.8%、3.9%、4.0%、4.1%、4.2%、4.3%、4.4%、4.5%、4.6%、4.7%、4.8%、4.9%、5.0%、5.1%、5.2%、5.3%、5.4%、5.5%、5.6%、5.7%、5.8%、5.9%、6.0%、6.1%、6.2%、6.3%、6.4%、6.5%、6.6%、6.7%、6.8%、6.9%、7.0%、7.1%、7.2%、7.3%、7.4%、7.5%、7.6%、7.7%、7.8%、7.9%、8.0%、8.1%、8.2%、8.3%、8.4%、8.5%、8.6%、8.7%、8.8%、8.9%、9.0%、9.1%、9.2%、9.3%、9.4%、9.5%、9.6%、9.7%、9.8%、9.9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、35%、40%、45%、50%、60%、65%、70%、75%、80%、85%、90%、95%或99%或其中可以推导出来的任何范围。在非限制性方面中,可以根据整个组合物的重量或体积计算百分比。本领域技术人员应当了解,所述浓度可以视向所公开的方法和组合物中添加、替换和/或减去化合物、药剂或活性成分而变化。
V.活性剂的调配
在一个实施方案中,本发明药剂提供包括本发明药剂的局部调配物。这样的包括活性剂的调配物将会含有典型地供局部传递使用的多种化合物和组合物。下面讨论用于制备局部调配物的药剂。
A.成膜剂
成膜剂是在干燥后可以在皮肤上产生连续的薄膜的材料或化合物。这能够增强组合物的持久性,同时也能减少皮肤的水分损失。CTFA手册第3卷第3187到3192页提供了可以用于本发明情形中的各类成膜剂,所有这些内容以引用的方式并入。所述成膜剂的非限制性实例包括聚硅氧烷-6、聚硅氧烷-8、聚硅氧烷-11、聚硅氧烷-14、VP/二甲聚硅氧烷基丙烯酸酯/聚氨基甲酰/聚乙二醇酯、VP/二甲基氨基乙基甲基丙烯酸酯共聚物、VP/二甲基氨基乙基甲基丙烯酸酯/聚氨基甲酰聚乙二醇酯、VP/二十烯共聚物、VP/十六碳烯共聚物、VP/甲基丙烯酰胺/乙烯基咪唑共聚物、VP/聚氨基甲酰聚乙二醇酯、VP/VA共聚物、聚酯-1、聚酯-2、聚酯-3、聚酯-4、聚酯-5、聚酯-7、聚酯-8以及聚酯-10。
B.含有酯的溶剂
酯类为酸类与醇类之间形成的共价化合物。它们可以在本发明情形中用来稳定和溶解药剂。CTFA手册第3卷第3079到3088页提供了可以用于本发明情形中的各类含有酯的溶剂,所有这些内容以引用的方式并入。所述溶剂的非限制性实例包括苯甲酸C12-15烷基酯、新戊二醇二庚酸酯、二丙二醇二苯甲酸酯和PPG-15硬脂酰醚苯甲酸酯。
C.胶凝剂
本发明的组合物可以被调配成透明凝胶。例如二甲聚硅氧烷/双异丁基PPG-20交联聚合物的胶凝剂可以用来形成基于凝胶的底料(primer)。此外,各类胶凝剂可获自DowCorning(Midland,Michigan(USA))。一个非限制性实例包括Dow Corning EL-8050ID,它是二甲聚硅氧烷/双异丁基PPG-20交联聚合物与异十二烷的掺合物。
D.其他皮肤调节剂和润肤剂
可以与本发明的组合物一起使用的皮肤调节剂和润肤剂的非限制性实例包括氨基酸、硫酸软骨素、双甘油、赤藓醇、果糖、葡萄糖、甘油聚合物、二醇、1,2,6-己三醇、蜂蜜、透明质酸、氢化蜂蜜、氢化淀粉水解产物、环己六醇、乳糖醇、麦芽糖醇、麦芽糖、甘露糖醇、天然保湿因子、PEG-15丁二醇、聚甘油基山梨糖醇、吡咯烷酮羧酸的盐、PCA钾盐、丙二醇、葡糖醛酸钠、PCA钠盐、山梨糖醇、蔗糖、海藻糖、尿素以及木糖醇。
其他实例包括乙酰化羊毛脂、乙酰化羊毛脂醇、丙烯酸酯/丙烯酸C10-30烷基酯交联聚合物、丙烯酸酯共聚物、丙氨酸、藻类提取物、巴巴多芦荟(aloe barbadensis)、巴巴多芦荟提取物、巴巴多芦荟凝胶、药蜀葵(althea officinalis)提取物、辛烯基琥珀酸淀粉铝、硬脂酸铝、杏(山杏(prunus armeniaca))仁油、精氨酸、精氨酸天冬氨酸盐、山金车(arnica montana)提取物、抗坏血酸、抗坏血酸棕榈酸酯、天冬氨酸、鳄梨(油梨(perseagratissima))油、硫酸钡、屏障鞘脂类、丁醇、蜂蜡、二十二醇、β-谷甾醇、BHT、桦木(欧洲桦)树皮提取物、琉璃苣(borago officinalis)提取物、2-溴代-2-硝基丙烷-l,3-二醇、金雀花(假叶树(ruscus aculeatus))提取物、丁二醇、金盏花(calendula officinalis)提取物、金盏花油、蜡大戟(candelilla)(小烛树(euphorbia cerifera))蜡、菜籽油、辛酸/癸酸三酸甘油酯、小豆蔻(elettaria cardamomum)油、巴西棕榈(巴西棕榈树(coperniciacerifera))蜡、角叉菜胶(角叉菜(chondrus crispus))、胡萝卜(daucus carota sativa)油、蓖麻(ricinus communis)油、神经酰胺、地蜡、鲸蜡硬脂醇聚醚-5、鲸蜡硬脂醇聚醚-12、鲸蜡硬脂醇聚醚-20、辛酸鲸蜡硬脂酸酯、鲸蜡醇聚醚-20、鲸蜡醇聚醚-24、乙酸鲸蜡酯、辛酸鲸蜡酯、棕榈酸鲸蜡酯、甘菊(洋甘菊(anthemis nobilis))油、胆固醇、胆固醇酯、羟基硬脂酸胆甾烯酯、柠檬酸、香紫苏(salvia sclarea)油、可可(theobroma cacao)脂、椰油醇-辛酸酯/癸酸酯、椰子(椰子树(cocos nucifera))油、胶原、胶原氨基酸、玉米(zea mays)油、脂肪酸、油酸癸酯、糊精、重氮咪唑烷基脲、二甲聚硅氧烷共聚醇、聚二甲基硅氧烷醇、己二酸二辛酯、丁二酸二辛酯、二聚季戊四醇六辛酸酯/六癸酸酯、DMDM乙内酰脲、DNA、赤藓醇、乙氧基二甘醇、亚油酸乙酯、蓝桉(eucalyptus globulus)油、月见草(oenotherabiennis)油、脂肪酸、果糖、明胶、野天竺葵(geranium maculatum)油、葡糖胺、葡萄糖谷氨酸盐、谷氨酸、甘油聚醚-26、甘油、二硬脂酸甘油酯、羟基硬脂酸甘油酯、月桂酸甘油酯、亚油酸甘油酯、肉豆蔻酸甘油酯、油酸甘油酯、硬脂酸甘油酯、硬脂酸甘油酯SE、甘氨酸、乙二醇硬脂酸酯、乙二醇硬脂酸酯SE、氨基多糖、葡萄(酿酒葡萄(vitis vinifera))籽油、榛(美洲榛(corylus americana))果仁油、榛(欧洲榛(corylus avellana))果仁油、己二醇、蜂蜜、透明质酸、红花(carthamus tinctorius)油、氢化蓖麻油、氢化椰油醇甘油酯、氢化椰子油、氢化羊毛脂、氢化卵磷脂、氢化棕榈油甘油酯、氢化棕榈仁油、氢化豆油、氢化牛脂甘油酯、氢化植物油、水解胶原、水解弹性蛋白、水解氨基多糖、水解角蛋白、水解大豆蛋白质、羟基化羊毛脂、羟脯氨酸、咪唑烷基脲、丁基氨基甲酸碘丙炔酯、硬脂酸异鲸蜡酯、硬脂酰硬脂酸异鲸蜡酯、油酸异癸酯、异硬脂酸异丙酯、羊毛脂酸异丙酯、豆蔻酸异丙酯、棕榈酸异丙酯、硬脂酸异丙酯、异硬脂酰胺DEA、异硬脂酸、乳酸异硬脂酰酯、新戊酸异硬脂酰酯、茉莉(白茉莉(jasminum officinale))油、荷荷芭(buxus chinensis)油、海草灰、夏威夷果(石栗(aleurites moluccana))果仁油、乳酰胺MEA、羊毛脂醇聚醚-16、羊毛脂醇聚醚-10乙酸酯、羊毛脂、羊毛脂酸、羊毛脂醇、羊毛脂油、羊毛脂蜡、薰衣草(狭叶熏衣草(lavandulaangustifolia))油、卵磷脂、柠檬(香橼(citrus medica limonum))油、亚油酸、亚麻酸、澳州坚果油(macadamia temifolia nut oil)、硬脂酸镁、硫酸镁、麦芽糖醇、母菊(洋甘菊(chamomilla recutita))油、甲基葡萄糖倍半硬脂酸酯、甲基硅烷醇PCA、微晶蜡、矿物油、貂油、黄褐色被孢霉油(mortierella oil)、乳酸十四烷酯、肉豆蔻酸十四烷酯、丙酸十四烷酯、新戊二醇二辛酸酯/二癸酸酯、辛基十二烷醇、肉豆蔻酸辛基十二烷酯、硬脂酰硬脂酸辛基十二烷酯、羟基硬脂酸辛酯、棕榈酸辛酯、水杨酸辛酯、硬脂酸辛酯、油酸、橄榄(油橄榄(olea europaea))油、橙(甜橙(citrus aurantium dulcis))油、棕榈树(油棕(elaeisguineensis))油、棕榈酸、双泛酰硫乙胺、泛醇、泛醇基乙基醚、石蜡、PCA、桃(prunuspersica)仁油、花生(落花生(arachis hypogaea))油、PEG-8C12-18酯、PEG-15椰油胺、PEG-150二硬脂酸酯、PEG-60异硬脂酸甘油酯、PEG-5硬脂酸甘油酯、PEG-30硬脂酸甘油酯、PEG-7氢化蓖麻油、PEG-40氢化蓖麻油、PEG-60氢化蓖麻油、PEG-20甲基葡萄糖倍半硬脂酸酯、PEG40脱水山梨糖醇全油酸酯、PEG-5大豆固醇、PEG-10大豆固醇、PEG-2硬脂酸酯、PEG-8硬脂酸酯、PEG-20硬脂酸酯、PEG-32硬脂酸酯、PEG40硬脂酸酯、PEG-50硬脂酸酯、PEG-100硬脂酸酯、PEG-150硬脂酸酯、十五酸内酯、胡椒薄荷(椒样薄荷(mentha piperita))油、矿脂、磷脂、多氨基酸多糖缩合物、聚甘油-3二异硬脂酸酯、聚季铵盐-24、聚山梨酸酯20、聚山梨酸酯40、聚山梨酸酯60、聚山梨醇酯80、聚山梨酸酯85、肉豆蔻酸钾、棕榈酸钾、山梨酸钾、硬脂酸钾、丙二醇、丙二醇二辛酸酯/二癸酸酯、丙二醇二辛酸酯、丙二醇二壬酸酯、丙二醇月桂酸酯、丙二醇硬脂酸酯、丙二醇硬脂酸酯SE、PVP、吡哆醇二棕榈酸酯、季铵盐-15、季铵盐-18锂蒙脱石、季铵盐-22、视黄醇、棕榈酸视黄酯、稻(水稻(oryza sativa))糠油、RNA、迷迭香(rosmarinus officinalis)油、玫瑰油、红花(carthamus tinctorius)油、鼠尾草(salviaofficinalis)油、水杨酸、檀香(白檀(santalum album))油、丝氨酸、血清蛋白、芝麻(sesamum indicum)油、丝粉、硫酸软骨素钠、透明质酸钠、乳酸钠、棕榈酸钠、PCA钠盐、聚谷氨酸钠、硬脂酸钠、可溶胶原、山梨酸、脱水山梨糖醇月桂酸酯、脱水山梨糖醇油酸酯、脱水山梨糖醇棕榈酸酯、脱水山梨糖醇倍半油酸酯、脱水山梨糖醇硬脂酸酯、山梨糖醇、大豆(野生大豆(glycine soja))油、鞘脂类、角鲨烷、角鲨烯、硬脂酰胺MEA-硬脂酸酯、硬脂酸、硬脂氧基二甲聚硅氧烷、硬脂氧基三甲基硅烷、十八醇、硬脂基甘草亭酸酯、硬脂醇庚酸酯、硬脂酸硬脂醇酯、向日葵(helianthus annuus)籽油、甜扁桃(prunus amygdalus dulcis)油、合成蜂蜡、生育酚亚油酸酯、新戊酸十三烷基酯、硬脂酸十三烷基酯、三乙醇胺、三硬脂酸甘油酯、尿素、植物油、水、蜡、小麦(triticum vulgare)胚芽油以及依兰依兰(canangaodorata)油。
E.抗氧化剂
可以与本发明的组合物一起使用的抗氧化剂的非限制性实例包括乙酰半胱氨酸、抗坏血酸多肽、二棕榈酸抗坏血酸酯、甲基硅烷醇果冻酸抗坏血酸酯、棕榈酸抗坏血酸酯、硬脂酸抗坏血酸酯、BHA、BHT、叔丁基氢醌、半胱氨酸、半胱氨酸HCl、二戊基氢醌、二叔丁基氢醌、硫代二丙酸三十二烷酯、二油酰基生育酚甲基硅烷醇、硫酸抗坏血酸酯二钠、硫代二丙酸二硬脂酰酯、硫代二丙酸二-十三酯、没食子酸十二酯、异抗坏血酸、抗坏血酸的酯、阿魏酸乙酯、阿魏酸、没食子酸酯、氢醌、硫代乙醇酸异辛酯、曲酸、抗坏血酸镁、磷酸抗坏血酸酯镁、甲基硅烷醇抗坏血酸酯、天然植物学抗氧化剂(例如绿茶或葡萄籽提取物)、去甲二氢愈创木酸、没食子酸辛酯、苯基硫代乙醇酸、生育酚磷酸抗坏血酸酯钾、亚硫酸钾、没食子酸丙酯、苯醌、迷迭香酸、抗坏血酸钠、亚硫酸氢钠、异抗坏血酸钠、焦亚硫酸钠、亚硫酸钠、过氧化物歧化酶、硫代乙醇酸钠、山梨醇缩糠醛、硫二甘醇、亚硫基二乙酰胺(thiodiglycolamide)、亚硫基二乙酸、氢硫基乙酸、硫代乳酸、硫代水杨酸、生育酚聚醚-5、生育酚聚醚-10、生育酚聚醚-12、生育酚聚醚-18、生育酚聚醚-50、托可索仑(tocophersolan)、生育酚亚油酸酯、生育酚烟酸酯、生育酚琥珀酸酯以及三(壬基苯基)亚磷酸酯。
F.结构剂
在其他非限制性方面中,本发明的组合物可以包括结构剂。结构剂在某些方面中,有助于向组合物提供流变特性以便促成组合物的稳定性。在其他方面中,结构剂还可以充当乳化剂或表面活性剂。结构剂的非限制性实例包括硬脂酸、棕榈酸、十八醇、鲸蜡醇、二十二醇、硬脂酸、棕榈酸、平均具有约1到约21个环氧乙烷单元的十八醇的聚乙二醇醚、平均具有约1到约5个环氧乙烷单元的鲸蜡醇的聚乙二醇醚以及其混合物。
G.乳化剂
在一些非限制性方面中,组合物可以包括一种或多种乳化剂。乳化剂可以减小相间界面张力并且改善乳液的调配和稳定性。乳化剂可以是非离子、阳离子、阴离子以及两性离子型乳化剂(参见McCutcheon’s(1986);美国专利5,011,681;4,421,769;3,755,560)。非限制性实例包括甘油酯、丙二醇酯、聚乙二醇脂肪酸酯、聚丙二醇脂肪酸酯、山梨糖醇酯、脱水山梨糖醇酸酐酯、羧酸共聚物、葡萄糖的酯和醚、乙氧基化醚、乙氧基化醇、磷酸烷基酯、聚氧乙烯脂肪醚磷酸盐、脂肪酸酰胺、酰基乳酸酯、皂类、TEA硬脂酸酯、DEA油醇聚醚-3磷酸酯、聚乙二醇脱水山梨糖醇单月桂酸酯(聚山梨酸酯20)、聚乙二醇5大豆固醇、硬脂醇聚醚-2、硬脂醇聚醚-20、硬脂醇聚醚-21、鲸蜡硬脂醇聚醚-20、PPG-2甲基葡萄糖醚二硬脂酸酯、鲸蜡醇聚醚-10、聚山梨醇酯80、磷酸鲸蜡酯、磷酸鲸蜡酯钾、二乙醇胺磷酸鲸蜡酯、聚山梨酸酯60、硬脂酸甘油酯、PEG-100硬脂酸酯以及其混合物。
H.含有硅氧烷的化合物
在非限制性方面中,含有硅氧烷的化合物包括分子主链是由交替的硅原子和氧原子组成并且侧基附接于硅原子的聚合产品家族中的任何成员。通过改变-Si-O-链长度、侧基以及交联反应,可以将硅氧烷合成到多种材料中。它们可以在稠度上从液体到凝胶直至固体有所不同。
可以用于本发明情形中的含有硅氧烷的化合物包括本说明书中所述的那些化合物或本领域技术人员已知的那些化合物。非限制性实例包括硅油(例如挥发性和不挥发性油)、凝胶以及固体。在优选方面中,含硅化合物包括硅油,例如聚有机硅氧烷。聚有机硅氧烷的非限制性实例包括二甲聚硅氧烷、环聚二甲基硅氧烷、苯基三甲基聚硅氧烷、三甲基甲硅烷基氨端聚二甲基硅氧烷、硬脂氧基三甲基硅烷或这些前述者与其他有机硅氧烷材料呈任何既定比率的混合物,以便获得所需的稠度和应用特性,这视预定应用而定(例如应用于特定区域,例如皮肤、毛发或眼睛)。“挥发性硅油”包括具有低汽化热的硅油,即每克硅油一般小于约50卡。挥发性硅油的非限制性实例包括:环聚二甲基硅氧烷,例如Dow Corning344Fluid、Dow Corning 345Fluid、Dow Corning 244Fluid和Dow Corning 245Fluid;挥发性硅7207(Union Carbide Corp.,Danbury,Conn.);低粘度二甲聚硅氧烷,即粘度为50cst或更小的二甲聚硅氧烷(例如,如Dow Corning 200-0.5cst Fluid的二甲聚硅氧烷)。这些Dow Corning Fluid可获自Dow Corning Corporation,Midland,Michigan。环聚二甲基硅氧烷和二甲聚硅氧烷分别是作为环状二甲基聚硅氧烷化合物和由三甲基甲硅烷氧基单元封端的完全甲基化的线性硅氧烷聚合物的混合物描述于CTFA化妆品成分字典(CosmeticIngredient Dictionary)(以引用的方式并入)的第三版本中。可以用于本发明情形中的其他非限制性挥发性硅油包括可以获自以下来源的那些硅油:General Electric Co.,Silicone Products Div.,Waterford,N.Y.以及SWS Silicones Div.of StaufferChemical Co.,Adrian,Michigan。
I.精油
精油包括源自草本植物、花卉、树木和其他植物的油类。这样的油类通常表现为植物细胞之间微小的液滴,并且可以通过为本领域技术人员所知的数种方法来提取(例如蒸汽蒸馏、花香提取法(即通过使用油脂来提取)、浸渍、溶剂萃取或机械加压)。当这些类型的油暴露于空气时,它们倾向于蒸发(即挥发性油)。因此,许多精油是无色的,但它们会因时间长久而氧化并且变暗。精油不溶于水,但可溶于醇、醚、固定油类(植物的)和其他有机溶剂中。精油中可见的典型物理性质包括自约160℃到240℃变动的沸点和在约0.759到约1.096范围内的密度。
精油通常根据发现有这种油的植物来命名。例如,玫瑰油或薄荷油分别是源自于玫瑰或薄荷植物。可以用于本发明情形中的精油的非限制性实例包括芝麻油、澳洲坚果油、茶树油、月见草油、西班牙鼠尾草油、西班牙迷迭香油、芫荽油、麝香草油、众香果油、玫瑰油、茴香油、香脂油、香柠檬油、玫瑰木油、雪松油、春黄菊油、撒尔维亚油、鼠尾草油、丁香油、柏树油、桉树油、小茴香油、海茴香油、兰丹油、香叶油、姜油、葡萄柚油、茉莉油、桧油、熏衣草油、柠檬油、香茅草油、白柠檬油、橘子油、甘牛至油、没药油、橙花油、橙油、广藿香油、胡椒油、黑胡椒油、橙叶油、松油、玫瑰花油、迷迭香油、檀香油、留兰香油、甘松油、香根油、冬青油或依兰依兰油。为本领域技术人员所知的其他精油也预期适用于本发明的情形。
J.增稠剂
增稠剂包括可以提高组合物粘度的物质。增稠剂包括可以提高组合物粘度但不会实质上改变组合物内的活性成分功效的那些增稠剂。增稠剂还可以提高本发明组合物的稳定性。
可以用于本发明情形中的其他增稠剂的非限制性实例包括羧酸聚合物、交联聚丙烯酸酯聚合物、聚丙烯酰胺聚合物、多糖和胶质物。羧酸聚合物的实例包括含有一个或多个源自丙烯酸、已被取代的丙烯酸以及这些丙烯酸和已被取代的丙烯酸的盐和酯的单体的交联化合物,其中交联剂含有两个或更多个碳-碳双键并且源自于多元醇(参见美国专利5,087,445;4,509,949;2,798,053)。市售羧酸聚合物的实例包括卡波姆(carbomer),其为与蔗糖或季戊四醇的烯丙基醚交联的丙烯酸均聚物(例如,CarbopolTM900系列,来自B.F.Goodrich)。
交联聚丙烯酸酯聚合物的非限制性实例包括阳离子和非离子聚合物。实例描述于美国专利5,100,660、4,849,484、4,835,206、4,628,078和4,599,379中。
聚丙烯酰胺聚合物(包括非离子聚丙烯酰胺聚合物,包括已被取代的有分支或无分支的聚合物)的非限制性实例包括聚丙烯酰胺、异链烷烃和月桂醇聚醚-7以及丙烯酰胺和已被取代的丙烯酰胺与丙烯酸和已被取代的丙烯酸的多嵌段共聚物。
多糖的非限制性实例包括纤维素、羧甲基羟乙基纤维素、乙酸丙酸羧酸纤维素、羟乙基纤维素、羟乙基乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、甲基羟乙基纤维素、微晶纤维素、纤维素硫酸钠以及其混合物。另一个实例是被烷基取代的纤维素,其中纤维素聚合物的羟基被羟烷基化(优选的是羟乙基化或羟丙基化)以形成羟烷基化纤维素,它接着进一步通过醚键而用C10-C30直链或支链烷基修饰。通常,这些聚合物是C10-C30直链或支链醇与羟烷基纤维素形成的醚。其他适用多糖包括硬葡聚糖,其包含(1-3)连接的葡萄糖单元的直链并且每三个单元有(1-6)连接的葡萄糖。
可以用于本发明情形中的胶质物的非限制性实例包括阿拉伯胶、琼脂、海藻胶、海藻酸、海藻酸铵、支链淀粉、海藻酸钙、角叉菜胶钙、肉碱、角叉菜胶、糊精、明胶、洁冷胶、瓜尔胶、瓜尔胶羟丙基三甲基氯化铵、锂蒙脱石、透明质酸、水合硅石、羟丙基几丁聚糖、羟丙基瓜尔胶、刺梧桐树胶、海草灰、刺槐豆胶、纳豆胶、海藻酸钾、角叉菜胶钾、丙二醇海藻酸酯、菌类植物胶、羧甲基葡聚糖钠、角叉菜胶钠、黄蓍胶、黄原胶以及其混合物。
K.媒剂
本发明的组合物可以并入到在所有类型的媒剂中有效的所有类型中。合适的媒剂的非限制性实例包括乳液(例如油包水、水包油包水、水包油、油包水包油、硅氧烷包水包油乳液)、乳膏剂、洗剂、溶液(水性和水醇性两者)、无水基质(例如唇膏和粉末)、凝胶剂以及软膏剂,或者通过将会为本领域技术人员所知的其他方法或前述方法的任何组合来实现(Remington’s,1990)。变化和其他适当的媒剂将会为有经验的技术人员所显而易见并且适用于本发明中。在某些方面中,重要的是以一定方式对化合物、成分和活性剂的浓度和组合进行选择,以至于这些组合在化学上相容并且不会形成会从成品中沉淀析出的复合物。
VI.制造物品
本发明预期使用VUAA1药剂来制造某些项目。材料可以是预先制成,并且使其浸渍、向其涂抹或喷涂药剂。或者,材料可以是在药剂存在下形成,以至于使药剂整体地合并到材料中。
例如,VUAA1可以用来涂布或浸渍各种制造物品,由此可以有助于将VUAA1传递到蚊虫环境中和/或防止物品使用者接触蚊虫。这样的物品包括网织物,例如用于将昆虫从住处(即窗和门道内)排除在外或将昆虫从特定位置(例如床上或房间)排除在外的类型。
其他制造物品包括包覆物或可以制成包覆物的织物。包覆物包括帽子、盖膜、遮罩、鞋和手套以及衬衫、裤子和内衣。其他物品包括衬垫,例如被单、毯子、枕套和褥垫。还有的其他物品包括帆布、帐篷、雨篷、风门片、幕布或布帘。
VII.药剂传递系统
A.雾化系统
在一个实施方案中,可以有利地使用雾化系统将本发明的活性剂分散到一环境中。所述环境可以是单个家族住宅院子以及街道、附近地区、分区、镇区或城市。雾化系统的实例显示于美国专利7,306,167和7,090,147以及美国专利公开案2006/0260183中,这些文献据此以引用的方式并入本文中。
B.饵料和球粒
在许多情况下,将会需要以固体形式施用本发明的药剂。害虫控制用固体组合物通常不易于挥发性散布活性剂,并且在有些情况下可以更容易地和方便地被施用;例如,害虫控制用固体组合物可以比液体更容易一些地从直升机或飞机或其他架高的运输工具降落到一大片水表面上。另外,当由高架的运输工具散布时,固体控制药剂被认为更能够穿透植物冠层(vegetative canopy)。
当需要形成用于蚊虫的固体组合物时,需要满足若干项准则。第一,害虫控制用固体组合物应具有足够的耐久性以允许控制用组合物可被散装输送,例如用火车或经由袋装运输来输送。第二,一般将包括载剂和活性控制剂的固体组合物必须与害虫目标区域环境相容;因此,所述载剂应当易于生物降解。第三,害虫控制用固体组合物当施加到水流中时或当以别的方式由水,例如雨水接触时,应当既容易又快速地释放控制剂。
现有技术已经提供了许多害虫控制用组合物。例如,美国专利6,391,328描述了一种用包括载剂、活性成分和包覆物的组合物处理生物体的方法。载剂材料据说包括二氧化硅、纤维素、金属氧化物、粘土、纸张、硅藻土、矿渣、疏水性材料、聚合物(例如聚乙烯醇)等等。活性成分的释放速率的控制据说是通过选择包覆材料来实现,这种包覆材料据说有脂肪酸、醇或酯。类似技术据称公开于以下文献中:美国专利6,387,386、6,350,461、6,346,262、6,337,078、6,335,027、6,001,382、5,902,596、5,885,605、5,858,386、5,858,384、5,846,553以及5,698,210(均由Levy提供给Lee County Mosquito Control District,FortMeyers,Fla.)。
另一种害虫控制用组合物公开于美国专利5,824,328、5,567,430、5,983,390以及4,418,534中。根据这些专利所表明的教示,以包括超吸收剂聚合物和惰性稀释剂的材料形式提供活化。
美国专利公开案2007/0160637公开了一种害虫控制剂,它是通过以下步骤来形成:提供多孔淀粉和吸收到多孔淀粉内部的活性控制剂,并且在热的存在下对多孔淀粉进行压制,以形成离散的多个粒子,包括一种或多种粘合剂以及一种或多种辅助吸收剂/填料。可以通过在商业制粒机中粒化来进行制备。这些粒子具有足够的耐久性以便能经受散装输送,例如用火车或袋装装运来输送,并且一旦与水接触后即可快速地释放控制剂,以至于例如当将害虫控制剂引入滞水中时可以释放控制剂。
VIII.实施例
包括以下实施例以展示本发明的优选实施方案。本领域技术人员应了解,以下实施例中所公开的技术代表本发明者发现能在实施本发明时很好地起作用的技术,并且因此可被认为构成本发明实施的优选模式。然而,根据本公开,本领域技术人员应了解,在不背离本发明的精神和范畴的情况下,可以在所公开的具体实施方案中作出许多改变,并且仍能获得相同或类似结果。
实施例1:材料和方法
细胞培养和Ca2+成像:在瞬时转染中,将OR克隆到pCI(Promega)中并且与Fu GENE6(Roche)一起转染到Flp-InTMT-RExTM293细胞系(Invitrogen)中。为了建立稳定细胞系,对能够表达AgORco以及常规型OR pcDNA5/FRT/TO(Invitrogen)的细胞培养表达载体进行修饰,以建立各自处于独立的CMV/TetO2启动子和BGH多腺苷酸化信号控制之下的两个个别表达盒。用已经修饰的pcDNA5质粒连同POG44(Flp重组酶表达质粒)一起转染细胞(如上所述)以有助于位点特异性重组。使用潮霉素(Hygromycin)B(Invitrogen)选择稳定细胞系。将细胞维持在补充有10%无四环素(Tetracycline)的FBS(HyClone)和15μg/ml杀稻瘟菌素(Blasticidin)的DMEM(Invitrogen)中。在荧光Ca2+测量中,将表达所关注的OR的稳定细胞系按20,000个细胞/孔接种于黑壁、涂有聚赖氨酸的384孔细胞培养板(Greiner)中并且用0.3μg/μl四环素(Sigma)处理过夜以诱导OR表达。在每一检测前,在37℃、5%CO2下,在检测缓冲液(20mM HEPES,IX HBSS)中用1.8μM氟代-4AM(Molecular Probes)、2.5mM丙磺舒(Probenecid)(Molecular Probes)使细胞负载染料,持续45分钟。在FDSS6000(Hamamatsu)中检测Ca2+动员(mobilization)。进行基线读数,持续20s,然后自动添加先前稀释于DMSO和检测缓冲液中的化合物中。将比率描述为最大反应/最小反应并且针对最大反应者对各反应进行归一化。
化学剂:VUAA1是购自Sigma-Aldrich的Rare Chemical Library(CAS#525582-84-7)。在印制时,无法自Sigma-Aldrich获得VUAA1。为了确保是由VUAA1而不是混合物中所存在的污染物引起观测到的活性,本发明者进行了制备型高效液相色谱分析(HPLC)。简单地来说,将20mg VUAA1溶解于甲醇与DMSO的50/50混合物中,并且在Phenomenex Luna 30×50mm C18制备型柱上用0.1%三氟乙酸(TFA)水溶液与乙腈梯度相结合来进行HPLC。合并适当的馏分并且使其通过TFA清除剂柱(Polymer labs,StratoSpheres SPE PL-HCO3MP-树脂)。用Biotage V10Roto-vap通过旋转蒸发来移除溶剂,得到白色粉末。随后将VUAA1再溶解于DMSO中并且正如所述进行检测。
化学材料的表征:1H-NMR(400MHz,DMSO-d6)d 8.73(d,J=1.8Hz,1H),8.65(dd,J=1.5,4.8Hz,1H),7.97(dt,J=1.9,8.0Hz,1H),7.49(dd,J=2.5,8.3Hz,1H),7.37(d,J=8.4Hz,2H),7.04(d,J=8.4HZ,2H),4.10(s,1H),3.95(q,J=7.2Hz,2H),2.43(q,J=7.6Hz,2H),1.13(t,J=8.0Hz,3H),1.04(t,J=8.0Hz,3H)。13C-NMR(400MHz,DMSO-d6)d 165.71,152.92,151.32,150.95,149.07,139.35,136.87,136.33,128.38,124.34,123.90,119.58,37.91,27.97,16.05,15.42。HRMS(m/z)[M]+C19H22N5OS的计算值:368.1544,实测值:368.1545。
HEK细胞中的膜片钳记录:用Axopatch 200b放大器(Axon Instruments)放大来自表达OR的HEK293细胞的电流并且通过Digidata 1322A(Axon Instruments)数字化。记录电生理学数据并且使用pCLAMP 10(Axon Instruments)进行分析。电极是由石英管材(SutterInstruments)制成并且被拉制到4-6MΩ以进行全细胞记录。向电极填充内部溶液(120mMKC1、30mM D-葡萄糖、10mM HEPES、2mM MgCl2、1.1mM EGTA以及0.1CaCl2(pH 7.35,280mOsm))。外部(槽)溶液含有130mM NaCl、34mM D-葡萄糖、10mM HEPES、1.5mM CaCl2、1.3mM KH2PO4以及0.5MgSO4(pH7.35,300mOsm)。将化合物稀释于外部溶液中,并且使用灌注笔(Perfusion Pencil,Automate Scientific)局部地灌注到记录细胞,并且用ValveLink8.2控制器(Automate Scientific)进行控制。在10kHz下对全细胞记录进行取样并且在5kHz下进行过滤。使用由标准玻璃毛细管(World Precision Instruments)拉制而成的10-15MΩ电极来获得外面向外的膜片并且用MF-830微型锻造仪(micro forge,Narishige)用火抛光。在20kHz下对单通道记录进行取样。将记录降低到1kHz并且在500Hz下进行低通过滤以便使用QuB(SUNY,Buffalo)进行显示和分析。
单一感觉器记录(Single sensillum recordings):对4-7天大、不食血并且用10%蔗糖和12/12光暗周期维持的雌性冈比亚按蚊进行单一感觉器记录。从冷麻醉过的雌虫移去足部、翅膀和触须,接着用细线束缚在双面胶上。将填充有感觉器淋巴林格氏液(Sensillar lymph ringer,SLR)(Xu,2005)的玻璃参考电极安置于其眼部并且使用填充有稀释于SLR中的DMSO或VUAA1的记录电极来刺穿其基底的感觉器。记录反应并且使用Syntech IDAC-4数字化,并且用AutoSpike软件(Syntech)分析。每一次记录使用新的玻璃记录吸移管。在12kHz下对数据进行取样。
实施例2-结果
作为一项正在进行的用于筛选会破坏嗅觉驱动的蚊虫行为的新颖小分子AgOR调节剂的基于细胞的钙成象筛选的一部分,本发明者鉴别出许多能活化表达AgOR10+AgORco的人类胚肾(HEK293)细胞的化合物。这些化合物之一(图3A),此处用VUAA1指示,引起与变构促效性一致的活性并且追踪其新颖性质。使用高分辨率质谱分析(HRMS)以及1H和13C NMR验证VUAA1的特性。当在基于板的钙成像系统中测试AgORco+AgOR10细胞时,VUAA1引起浓度依赖性反应,而这在对照细胞中则观察不到(图3B)。在进一步研究之后,VUAA1被证实同样能够活化其他AgORco7+AgOR10细胞系(未发表数据)。由于AgORco是这些功能性反应中所共有的要素,因此本发明者假定VUAA1是一种潜在的AgORco促效剂。
为了测试VUAA1直接促进AgORco的假设,在表达AgORco+AgOR10的细胞以及稳定地单独表达AgORco的HEK293细胞中检验全细胞膜片钳反应。在这些实验中,VUAA1在表达AgORco+AgOR10和表达AgORco的两种细胞中均引起浓度依赖性向内电流(图3D到图3E)。AgORco+AgOR10细胞中的VUAA1依赖性电流类似于由施加苯甲醛(即AgOR10的一种正构促效剂)所引起的电流。(图3C)(Wang,2010;Carey,2010)。相较于AgORco细胞,AgORco+AgOR10细胞对VUAA1更敏感,在-5.0logM(即AgORco无反应的一个浓度)下产生向内电流。由VUAA1诱导的所有电流具有AgORco依赖性;在对照细胞中则没有观测到反应。为了研究VUAA1促效性的特异性,本发明者分别用黑腹果蝇(Drosophila melanogaster)和烟芽夜蛾(Heliothisvirescens)的AgORco直系同源物,即DmOR83b和HvOR2瞬时转染HEK细胞。在表达任一直系同源物的细胞中,VUAA1引起类似于表达AgORco的细胞的强大的向内电流(图3F)中。这些结果证明VUAA1是一种广谱的83b家族促效剂,能够活化多个昆虫目类之内以及之间的非常规的OR。这种活性与它们的高序列一致性(与DmOR83b为76%并且与HvOR2为67%)一致并且证明了功能性重叠(Jones等人,2005)。
为了进一步研究AgORco7的传导性质,本发明者测定了AgORco+AgOR10复合物以及AgORco自身的电流-电压关系。在表达AgORco+AgOR10的细胞中由VUAA-1或苯甲醛诱导的电流以及在AGORco细胞中由VUAA-1诱导的电流均几乎对称(图4A到图4D和图5A到图5D)。AgORco+AgOR10复合物的逆转电位是-2.9士1.4mV(苯甲醛)和-4.8士3.0mV(VUAA1),而单独AgORco在VUAA1存在下的逆转电位则为+0.4士1.1mV(平均值士标准偏差,图4A到图4C)。这些电流-电压关系并没有指示任何电压依赖性门控性,并且接近零的逆转电位与先前有关昆虫OR复合物的表明非选择性阳离子导电率的报导一致(Sato等人,2008;Wicher等人,2008)。本发明者接着研究VUAA1反应是否会由钌红(RR)(即一种先前发现能阻断昆虫OR电流的混杂的阳离子通道阻断剂)减弱。施加RR使AgOrco+AgOR10细胞由苯甲醛和VUAA1引起的电流分别降低87.8士1.8%和68.3士2.8%(图5A到图5D),而RR使AgORco细胞的VUAA1反应降低79.4士4.0%(图5C到图5D)。除了证明AgORco+AgOR10复合物和单独AgORco充当功能性配体门控型离子通道之外,这些研究还显示VUAA1引起类似于响应于气味的那些电流的AgOR电流。为了测定VUAA1的广谱特异性,本发明者针对另一个非选择性阳离子通道,即瞬时受体电位香草酸受体1(TRPV1)测试了VUAA1(Caterina,1997;Bohlen,2010)。辣椒素在这些HEK细胞中引起强大反应,但VUAA1并非如此(图7A到图7F)。这些结果证明VUAA1对83b直系同源物具有特异性,并且VUAA1并不能广谱地活化所有阳离子通道。
本发明者接着验证AgORco的活化是否涉及基于第二信使的信号传导,已经报导这会促成昆虫嗅觉的信号传导(Wicher,2008)。在与先前公开的报导(Sato等人,2008)一致的这些研究中,两种环核苷酸类似物(8-Br cAMP和8-Br cGMP)不能在AgORco或AgORco+AgOR10细胞中激起全细胞电流,但在两种情况下OR功能分别是由随后施加VUAA1和苯甲醛来验证(图8A到图8D)。尽管常规的OR与AgORco之间的信号传递的确切机制仍然未知,但重要的是注意到所有通道性质在AgORco与AgOrco+AgOR10复合物之间以及本身内部是一致的。综合起来,数据表明AgORco的通道性质当其与其他AgOR复合时并未发生显著改变,并且AgORco的促离子电导率是功能性AgOR复合物的主要信号分量。
在下一组研究中,从表达AgORco的细胞切取外面向外的膜片以检验由VUAA1激起的单通道电流(图5A)。此处,在VUAA1刺激之前观测到自发的通道开放,但概率极低(P0=0.02)(图5B)。在施加VUAA1持续5s的期间,通道开放概率增加到Po=0.38(图5C)。在促效剂洗脱(washout)之后,通道开放概率降低到0.00(图5D)。AgORco的平均单位电流是1.3士0.3pA(平均值士标准偏差)(图5C,插图),这与早先有关昆虫OR的单通道研究(Sato等人,2008)一致。综合起来,这些数据证实我们的如下假设:VUAA1可以在不存在其他细胞内组分的情况下促进AgORco并且另外证实VUAA1作为AgORco和其他OR83b家族成员的直接促效剂的作用。
本发明者接着对雌性冈比亚按蚊成虫进行了单一单位的细胞外电生理学记录以测定VUAA1是否会体内活化表达AgORco的嗅觉受体神经元(ORN)。表达AgORco和常规的OR的ORN被封闭在存在于嗅觉组织上的毛发样感觉器之内。在下颚须上发现的高度典型的头状突起(Cp)感觉器含有两个ORco表达神经元(CpB和CpC)以及CO2敏感性神经元(CpA),后者不表达AgORco(Lu等人,2007)。CpA明显有别于CpB/C之处为它的较大动作电位振幅。CpB和CpC的动作电位振幅要小得多并且在一些标本中彼此很难区分;因此,格化贮存(binned)CpB和CpC神经元的峰活性以进行数据分析。相应地,本发明者将会预期如果VUAA1是一种特异性AgORco促效剂,那么它应能有选择地增加CpB和CpC神经元的峰频率,但对CpA反应无影响。
归因于其相对较高的分子量,VUAA1的挥发性传递不可行。因此,利用玻璃记录电极直接地向每个感觉器添加VUAA1,其中VUAA1以剂量依赖性方式使CpB/C神经元的峰频率增加;单独媒剂则没有影响(图6A、图6B、图6D)。在刺穿每个感觉器之后立即观测到有差异的CpB/C峰活性,表明化合物扩散到感觉器中的速率为毫秒数量级(图6A、图6B、图6D)。在每一次检测完成时,向感觉器传递CO2脉冲以测试VUAA1是否影响CpA神经元;与表达AgORco的CpB/C神经元的反应性形成对比,CpA活性在媒剂和/或VUAA1存在下没有变化(图6A、图6B、图6D)。这些数据证明VUAA1能够体内特异性地活化表达AgORco的神经元。此外,VUAAl体内活化表达AgORco的细胞的能力证明AgORco是易接近的生物学标靶,它不会直接被嗅觉信号转导中所涉及的其他蛋白质或辅因子遮掩。因而,VUAA1介导的调节作用可以作为一个概念验证的证明来表明:AgORco是一个可行的标靶而用于开发行为上破坏嗅觉的化合物(BDOC),它们能促进减少疟疾的计划。
尽管本发明者不能排除最终的鉴别,但目前没有证据能证实存在有天然存在的AgORco配体,这表明AgORco缺乏其他配体门控型离子通道所共有的典型正构结合位点。在对AgORco的结构分析未有更多进展的情况下,关于VUAA1门控机制以及它是否以类似于异聚OR复合物的经典OR依赖性活化的方式起作用很难作出假设。然而,显然,AgORco是促离子性配体门控型离子通道。
为了验证呈非挥发性形式的VUAA1是否还能激起冈比亚按蚊的行为反应,本发明者针对个别幼虫期蚊虫通过采用最近在Vanderbilt开发的基于嗅觉的生物检测(描述于Liu等人,2010)来测试了对VUAA1的行为反应。这些方法是非侵袭性的,并且易于使用完全自动化的配置用照相机/软件系统(Noldus Information Technology来执行以定量蚊虫幼虫响应于均匀浓度的化学剂的总体活动。在这些检测中,增加的总体活动可以解释为厌恶反应(类似于不安),这与由市售驱虫剂(例如DEET)激起的反应一致。
关于VUAA1,这些研究(图9)表明VUAA1激起冈比亚按蚊幼虫与驱避性一致的强大反应,并且幼虫对VUAA1的反应临限值(左起第三到第八柱条)比对DEET的反应临限值(从左边柱条算起第九到第十一柱条)低5个数量级。此外,使用针对AgORco的siRNA进行的基因沉默研究证明对VUAA的幼虫敏感性取决于AgORco表达。此处,用AgOrco siRNA(它们使AgORcomRNA水平降低40倍)处理过的幼虫不再对VUAA1刺激物起反应,而接受空白对照(mock)或非特异性siRNA对照注射的幼虫则保持它们对VUAA1的高敏感性。
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根据本发明无需过度的实验即可以制成和执行本文所公开和要求的所有组合物和方法。尽管已经就优选实施方案而言描述了本发明的组合物和方法,但本领域技术人员应显而易知,在不背离本发明的概念、精神和范畴的情况下,可以对本文所述的组合物和/或方法以及本文所述的方法的步骤或步骤序列施加变更。更具体地说,显然,在能获得相同或类似结果时,可以用在化学上和生理学上均相关的某些药剂替代本文所述的药剂。本领域技术人员显而易知的所有这些类似替代和修改应认为属于如由随附权利要求书所定义的本发明的精神、范畴和概念之内。
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Claims (17)
1.一种方法,所述方法包括将具有OR83b细胞表面嗅觉受体的昆虫暴露于以下化合物:
或其盐,由此激活所述受体。
2.根据权利要求1所述的方法,其中激活所述受体破坏昆虫寻找宿主的行为。
3.根据权利要求1所述的方法,其中所述昆虫是吸血昆虫。
4.根据权利要求1所述的方法,其中所述昆虫是蚊虫。
5.一种方法,所述方法包括将AgOR7暴露于以下化合物:
或其盐,由此激活所述AgOR7。
6.根据权利要求5所述的方法,其中所述AgOR7在体外。
7.根据权利要求6所述的方法,其中所述AgOR7在培养的细胞中。
8.根据权利要求5所述的方法,其中所述AgOR7在体内。
9.根据权利要求8所述的方法,其中所述AgOR7在昆虫内。
10.一种组合物,所述组合物包含以下化合物:
或其盐,和
一种或更多种成膜剂、含有酯的溶剂、胶凝剂、皮肤调节剂、润肤剂、抗氧化剂、结构剂、乳化剂、含有硅氧烷的化合物、精油、增稠剂和/或媒剂。
11.根据权利要求10所述的组合物,所述组合物包含一种或更多种雾化器、胶凝剂、润肤剂、乳化剂、精油和/或媒剂。
12.一种物品,所述物品包含以下化合物:
其中所述物品选自雾化系统、饵料、球粒、帆布、帐篷、雨篷、风门片、幕布和布帘。
13.一种物品,所述物品包含化合物
的盐,
其中所述物品选自雾化系统、饵料、球粒、织物、包覆物、衬垫、帆布、帐篷、雨篷、风门片、幕布和布帘。
14.根据权利要求13所述的物品,所述物品选自织物、包覆物和衬垫。
15.根据权利要求13或14所述的物品,其中所述织物是网织物。
16.一种方法,所述方法包括抑制气传昆虫中的宿主靶向功能,所述方法包括使用VUAA1。
17.如权利要求16所述的方法,其中所述昆虫是蚊虫。
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