酰胺与氨基酸聚合(ProTide前药技术——从概念到临床)

浣滆€咃細Aggiechen

鏍歌嫹绫昏嵂鐗╁湪鑲跨槫銆佹劅鏌撴€х柧鐥?鐥呮瘨濡侶SV銆丠IV銆丠BV銆丠CV鎴栫湡鑿屾劅鏌?绛夐鍩熷簲鐢ㄥ箍娉涖€傚叾浣滅敤闈剁偣澶氫负DNA鑱氬悎閰舵垨RNA閫嗚浆褰曢叾锛屾牳鑻风被鑽墿涓€鑸ā鎷熷ぉ鐒舵牳鑻风殑缁撴瀯锛岀珵浜夋€у湴浣滅敤浜庨叾娲绘€т腑蹇冿紝宓屽叆姝ｅ湪鍚堟垚鐨凞NA鎴朢NA閾句腑锛屽共鎵版牳閰镐唬璋€傛牳鑻风被鑽墿杩涘叆缁嗚優鍚庡湪閰剁殑浣滅敤涓嬬粡涓夋纾烽吀鍖栵紝寰楀埌鍏锋湁鐢熺墿娲绘€х殑涓夌７閰歌鐢熺墿鑰屽彂鎸ヨ嵂鏁堬紝鍏朵腑鍗曠７閰稿寲鏄檺閫熸楠わ紝鍥犳閫氬父鍦ㄦ牳鑻风被鑽墿涓洿鎺ュ紩鍏ュ崟纾烽吀鎴栫７閰搁叝鍩哄洟銆傛棭鏈熻璁＄殑纾烽吀鎴栫７閰搁叝琛嶇敓鐗╁洜鍏舵瀬鎬уぇ闅句互閫氳繃缁嗚優鑶滐紝纾?姘ч敭浠ｈ阿绋冲畾鎬ц緝宸瓑闄愬埗浜嗗簲鐢ㄣ€備负瑙ｅ喅绫昏嵂鎬ч棶棰樺湪璇ョ被鑽墿璁捐涓紝鍓嶈嵂绛栫暐琚箍娉涢噰鐢ㄣ€?/p>

ProTide鍓嶈嵂鎶€鏈槸鏍歌嫹绫昏嵂鐗╅鍩熷簲鐢ㄦ渶鎴愬姛鐨勫墠鑽妧鏈箣涓€銆傚叾璁捐鍘熺悊鏄皢鏍歌嫹鑶﹂吀/纾烽吀绫昏嵂鐗╁垎鍒€氳繃纾烽叝閿?纾烽叞鑳洪敭(鑺冲熀妯″潡/姘ㄥ熀閰搁叝鍩烘ā鍧?涓庢瀬鎬у熀鍥㈣繛鎺ュ舰鎴愮７閰?纾烽叞鑳哄墠鑽紝閫氳繃鎺╄斀鏋佹€у熀鍥㈡潵闄嶄綆鍒嗗瓙鏋佹€у鍔犻€忚啘鎬э紝褰撳墠鑽惛鏀惰繘鍏ヤ綋鍐呭悗鍐嶇粡鐗瑰畾閰舵按瑙ｉ噴鏀惧師鍨嬭嵂鐗┿€侳DA宸叉壒鍑嗕袱涓狿roTide鍓嶈嵂锛氭浛璇虹闊﹁壘鎷夐厷鑳?Tenefovir Alafenamide锛孴AF)鍜岀储闈炲竷闊?Sofosbuvir)銆?/p>

鍥続锛氭牳鑻风被鑽墿閫氳繃鏍歌嫹杞繍浣撹繘鍏ョ粏鑳炲苟琚叾纾烽吀鍖栦骇鐢熶笁纾烽吀鍖栨椿鎬т骇鐗╋紱B锛氭牳鑻峰崟纾烽吀鑽墿鏋佹€уぇ锛岄€忚啘鎬у樊锛岀敓鐗╁埄鐢ㄥ害浣庯紱C锛歅roTide鍓嶈嵂鍙婁笂甯傝嵂鐗┿€?/p>

ProTide鍓嶈嵂鎶€鏈殑璇炵敓鍜屾紨鍖?/p>

ProTide鎶€鏈渶鏃╁彲杩芥函鍒?0涓栫邯80骞翠唬锛屾棬鍦ㄥ皢纾烽吀鏋佹€у熀鍥㈤殣钄戒娇鑽墿鍦ㄧ敓鐞哖H鏉′欢涓嬪憟涓€э紝杩涜€屽鍔犺嵂鐗╁惛鏀躲€?0澶氬勾鐨勫彂灞曞彲鎸夌粨鏋勭壒寰佸垎涓哄涓嬭〃鎵€绀哄叚涓樁娈碉紝浠庣畝鍗曞湴寮曞叆鐑峰熀褰㈡垚纾烽吀閰€愭笎婕斿彉涓哄紩鍏ヨ姵鍩哄拰姘ㄥ熀閰搁叝鐨凱roTide鎶€鏈€?/p>

ProTide鍓嶈嵂鐨勫悎鎴?/p>

ProTides鍚堟垚鏈変笁绉嶄笉鍚岀殑绛栫暐锛?/p>

(1)鏍歌嫹涓庝簩鑺冲熀浜氳啨閰搁叝鍋惰仈闅忓悗姘у寲鑳哄寲锛?/p>

(2)鏍歌嫹涓庣７閰版隘鍙嶅簲锛?/p>

(3)鏍歌嫹纾烽吀鑺抽叝涓庢皑鍩洪吀缂╁悎銆?/p>

鏂规(2)鏄渶甯歌鐨勫悎鎴愭柟娉曪紝璇ユ柟娉曞父鐢ㄥ彅涓佸熀姘寲闀?tBuMgCl)鎴朜-鐢插熀鍜攽(NMI)鍋氱⒈(纰辨€BuMgCl>NMI)锛屽弽搴旇捣濮嬪簳鐗╀笉鍚屾墍鐢ㄧ⒈鏈夋墍宸紓锛涙澶栧弽搴斾骇鐢熺殑鏄潪瀵规槧寮傛瀯浣撴贩鍚堢墿锛屼竴浜涙儏鍐典笅闈炲搴斿紓鏋勪綋鍏锋湁鐩镐技鐨勬椿鎬ф棤闇€鍒嗙锛涗篃鏈変竴浜涙儏鍐甸潪瀵瑰簲寮傛瀯浣撲唬璋㈤€熺巼鏈夋墍宸埆锛屼絾闈炲搴斿紓鏋勪綋鐨勫垎绂绘槸宸ㄥぇ鎸戞垬銆?/p>

浠ユ牳鑻峰崟纾烽吀/鍗曠７閰搁叝涓哄簳鐗╁埗澶嘝roTide涔熸湁涓夌鏂规硶锛氣憼灏嗘牳鑻风７閰歌浆鍖栦负浜屾隘纾烽吀閰紝闅忓悗鍔犲叆1:1鐨勮嫰閰氬拰姘ㄥ熀閰搁叝锛涒憽鏍歌嫹纾烽吀涓庤嫰閰氬湪DCC鏉′欢涓嬬缉鍚堝悗浜х墿杞寲涓烘隘纾烽吀閰紝鏈€鍚庡姞鍏ユ皑鍩洪吀閰紱鈶㈠凡鏍歌嫹纾烽吀浜岃嫰閰仛璧峰搴曠墿锛屽厛姘磋В涓€涓嫰閰紝闅忓悗涓庢皑鍩洪吀閰缉鍚堛€?/p>

鍥撅細ProTide鍚堟垚鏂规

ProTide鍓嶈嵂鐨勪唬璋?/p>

ProTide鍓嶈嵂鍦ㄤ綋鍐呴噴鏀惧師鑽殑鏈哄埗锛氬墠鑽繘鍏ヤ綋鍐呭悗锛屼富瑕佺粡缁勭粐铔嬬櫧閰禔 (cathepsin A)灏嗘皑鍩洪吀閰按瑙ｄ负姘ㄥ熀閰革紝鍦ㄧ敓鐞哖H鏉′欢涓嬫皑鍩洪吀涓殑缇у熀璐熺瀛愯繘鏀荤７鍘熷瓙鍚屾椂鑺冲熀绂诲幓褰㈡垚浜斿厓鐜紝姘村垎瀛愪娇浜斿厓鐜腑闂翠綋杩涗竴姝ュ紑鐜紝寮€鐜骇鐗╁湪纾烽叝閰?纾烽叞鑳洪叾浣滅敤涓嬫皑鍩洪吀姘磋В閲婃斁鍗曠７閰稿師鑽紝鍚庣粡涓ゆ纾烽吀鍖栧緱鍒板叿鏈夌敓鐗╂椿鎬х殑涓夌７閰稿寲琛嶇敓鐗┿€?/p>

鍥撅細ProTide鍓嶈嵂鎶€鏈綋鍐呴檷瑙ｉ噴鏀惧師鑽殑鏈哄埗

ProTide鍓嶈嵂鎶€鏈湪鑽墿鐮斿彂涓殑搴旂敤

闄や簡宸蹭笂甯傜殑2涓狿roTide鍓嶈嵂锛岀洰鍓嶈繕鏈?0浣欎釜鑽墿澶勪簬涓村簥鐮旂┒闃舵銆?/p>

鍥撅細閲嶈鐨勫浜庝复搴婇樁娈电殑ProTide鍓嶈嵂

*ProTide鍓嶈嵂鎶€鏈彂鏄庝汉McGuigan鏁欐巿浜?015骞村姞鐩烴uCana Biomed鍏徃鎷呬换棣栧腑绉戝瀹讹紝鑷村姏鎵撻€犳姉鑲跨槫鑽墿棰嗗煙鐨凣ilead锛屼笉杩囬仐鎲剧殑鏄?016骞?鏈圡cGuigan鏁欐巿鍥犵檶鐥囦笉娌昏嫳骞存棭閫濄€?/strong>