張緒穆：年輕學(xué)者一定要有開(kāi)創(chuàng)一個(gè)領(lǐng)域的磅礴大氣

文/吳星鐸 譯/張佳藝

“解決科學(xué)難題，同時(shí)造福人類(lèi)?！薄敖淌谧龀鰜?lái)的成果，不僅能放在書(shū)架上，更能放在貨架上，書(shū)架貨架都要上?！边@是采訪張緒穆院士印象最深的兩句話。

2023年5月28日上午，第二期國(guó)際院士講堂開(kāi)講，張緒穆院士帶來(lái)《中國(guó)健康醫(yī)藥產(chǎn)業(yè)化道路：不對(duì)稱(chēng)催化技術(shù)及在制藥工業(yè)中的應(yīng)用》的主題分享。

在國(guó)際院士講堂的前一天，張緒穆院士接受了筆者專(zhuān)訪。在小分子藥領(lǐng)域、手性現(xiàn)象中自由徜徉，讓筆者對(duì)張?jiān)菏康膶W(xué)者風(fēng)范、厚重睿智印象深刻，并被深深觸動(dòng)和感染。

從諾獎(jiǎng)到師門(mén)緣分

話題從2022年剛剛獲得諾貝爾化學(xué)獎(jiǎng)的美國(guó)化學(xué)家巴里·夏普萊斯（K.Barry Sharpless）展開(kāi)。夏普萊斯是張緒穆的同門(mén)師兄，是第二位兩次獲得諾貝爾化學(xué)獎(jiǎng)的科學(xué)家。

“夏普萊斯在2001年獲得的諾貝爾獎(jiǎng)是關(guān)于‘不對(duì)稱(chēng)化學(xué)合成’，這次是關(guān)于‘點(diǎn)擊化學(xué)和生物正交合成’。”張緒穆介紹說(shuō)，當(dāng)年第一次獲得諾獎(jiǎng)時(shí)夏普萊斯已經(jīng)年滿60歲，張緒穆受邀參加了他在圣地亞哥舉辦的60歲生日會(huì)，這位師兄并沒(méi)有止步于其在手性化學(xué)領(lǐng)域的成就，很快就開(kāi)啟了一個(gè)新的方向，進(jìn)入生物領(lǐng)域?！岸潭?0年時(shí)間，又開(kāi)辟了一個(gè)全新的研究領(lǐng)域，這是科學(xué)創(chuàng)新的典范?！睆埦w穆說(shuō)。

“Solve scientific problems while benefiting mankind.”“The professors’ achievements are not only on the bookshelves but also on the goods shelves.” These two impressive sentences come from an interview with academician Zhang Xumu.

On the morning of May 28, 2023, academician Zhang Xumu delivered a theme presentation of “The Road to China’s Health Medicine Industrialization:Asymmetric Catalysis Technology and its Application in the Pharmaceutical Industry” on the second phase of the International Academician Forum.

The day before the International Academician Forum,academician Zhang Xumu received an exclusive interview with the author. In the small molecules and chiral phenomenon field, the author was deeply impressed by his scholarly style and wisdom and was deeply touched and infected.

From Nobel Prize to predestination of taking the same master

The conversation started with K. Barry Sharpless, an American chemist who won the Nobel Prize in Chemistry in 2022. Zhang Xumu studied under the same master with Sharpless who won the Nobel Prize in Chemistry twice.

“The Nobel Prize Sharpless won in 2001 was for‘Asymmetric Chemical Synthesis’ and this time for ‘Click Chemistry and Bioorthogonal Synthesis’.” Zhang Xumu explained that Sharpless had turned 60 when he first won the Nobel Prize. Zhang Xumu was invited to his 60thbirthday party in San Diego. Sharpless didn’t stop at the accomplishments in chiral chemistry but soon opened up a new biology chapter. “To open up another wholly new field of research in just 20 years is an example of scientific innovation.” Zhang Xumu said.

夏普萊斯與美國(guó)化學(xué)家卡羅琳·貝爾托西（Carolyn P.Bertozzi）、丹麥化學(xué)家莫滕·梅爾達(dá)（Morten P.Meldal）共享了2022年的諾貝爾化學(xué)獎(jiǎng)。在張緒穆看來(lái)，“夏普萊斯因?yàn)橹耙呀?jīng)獲得了諾貝爾獎(jiǎng)，他的影響力是最大的，貝爾托西排在第二。梅爾達(dá)獨(dú)立做出了與夏普萊斯差不多同樣的工作?！?/p>

張緒穆認(rèn)為，“點(diǎn)擊化學(xué)”（Click Chemistry）的名稱(chēng)體現(xiàn)了師兄一貫主張的“大道至簡(jiǎn)”?！包c(diǎn)擊化學(xué)”又被稱(chēng)為“鏈接化學(xué)”，實(shí)質(zhì)上是通過(guò)鏈接各種小分子來(lái)合成復(fù)雜的大分子，就像上車(chē)扣上安全帶一樣，便捷有效。夏普萊斯之所以有這樣的構(gòu)想，其實(shí)也是來(lái)自大自然的啟發(fā)。大自然就像一個(gè)有著神奇能力的化學(xué)家，它通過(guò)少數(shù)的單體小構(gòu)件，合成豐富多樣的復(fù)雜化合物。

張緒穆說(shuō)，“點(diǎn)擊化學(xué)”的奠基性論文于2000年8月提交給《德國(guó)應(yīng)用化學(xué)》雜志，沒(méi)有一個(gè)評(píng)審專(zhuān)家認(rèn)為該篇文章應(yīng)該被接收發(fā)表，經(jīng)過(guò)申訴后雜志的主編愿意推翻負(fù)面評(píng)論，2001年5月《點(diǎn)擊化學(xué)：通過(guò)幾個(gè)好的反應(yīng)實(shí)現(xiàn)分子功能》發(fā)表。該篇文章是目前合成化學(xué)領(lǐng)域引用量最高的一篇論文?！氨娙私宰砦要?dú)醒。一定要堅(jiān)持真理。真理有時(shí)候就是掌握在少數(shù)人手上，一定要對(duì)自己有信心?！睆埦w穆說(shuō)。

在張緒穆看來(lái)，夏普萊斯“大道至簡(jiǎn)”的研究理念使得他總能抓住科學(xué)問(wèn)題的核心，做出最簡(jiǎn)單、最有用的科研成果。夏普萊斯的“KISS”（KISS：Keep it Simple, Stupid.），正是“大道至簡(jiǎn)”理念的體現(xiàn)。

另一位對(duì)張緒穆有影響的師兄，是2005年因?yàn)橄N復(fù)分解反應(yīng)獲得諾貝爾化學(xué)獎(jiǎng)的羅伯特·格拉布斯（Robert H.Grubbs），“成立公司容易，要賺錢(qián)不容易。要有情懷，對(duì)世界產(chǎn)生巨大的影響力。此外，一定要把知識(shí)產(chǎn)權(quán)搞干凈?！备窭妓沟姆胃?，讓張緒穆受益匪淺。

Sharpless shared the 2022 Nobel Prize in Chemistry with American chemist Carolyn P. Bertozzi and Danish chemist Morten P. Meldal. In Zhang Xumu’s opinion, “Sharpless had the most influence because he had already won the Nobel Prize. Bertozzi came in second. Meldal independently did almost the same work as Sharpless.”

According to Zhang Xumu, “Click Chemistry” reflects the “Greatest truths always turn out to be simple.” “Click Chemistry,” also known as “Link Chemistry,” is essentially the synthesis of complex macromolecules by linking various small molecules, which is as convenient and effective as buckling up in a car. The reason why Sharpless has such a conception is inspired by nature. Nature is like a chemist with the magical ability to synthesize a wide variety of complex compounds through a small number of small monomer components.

Zhang Xumu said the seminal “click chemistry”paper submitted to theAngewandte Chemie International Editionin August 2000 was declined for publication. After appeals, the editor-in-chief was willing to override the negative comments and publish Click Chemistry: Molecular Functionality through a Few Good Reactions in May 2001.The article is now one of the most highly cited papers in synthetic chemistry. “Keep sober, especially when others are confused. Always stick to the truth. A minority sometimes seizes the truth, so be confident in oneself.” Zhang Xumu said.

In Zhang Xumu’s opinion, Sharpless’s research philosophy of “greatest truths always turn out to be simple”has enabled him to grasp the core of scientific problems and make the most straightforward and valuable results.Sharpless’s “KISS” (KISS: Keep it Simple, Stupid.) is the embodiment of the concept that “greatest truths always turn out to be simple”.

Another senior fellow apprentice who influenced Zhang Xumu is Robert H. Grubbs, who won the Nobel Prize in Chemistry in 2005 for the olefin complex decomposition reaction. “Setting up a company is easy but uneasy to make money. Be full of emotion and have a huge impact on the world. Additionally, keep the intellectual property clear.”Grubbs’s heartfelt words benefited Zhang Xumu a lot.

In November 2015, at the invitation of Zhang Xumu,Grubbs was appointed chairman of the Academic Advisory Board of the Department of Chemistry of the Southern University of Science and Technology (SUSTech) and planned to establish the Grubbs Institute at SUSTech, with Grubbs as the honorary dean, and Zhang Xumu as the founding executive dean. Based on SUSTech, the institute will set up a new medicine research center, a new material research center, and a new energy research center, vigorously introduce high-end talents from all over the country and even the world, and carry out subversive original innovation in the field of basic research, to vigorously promote the basic research and industrial development of Shenzhen and even China in the areas of new medicine, new materials, and new energy.

2015年11月，應(yīng)張緒穆邀請(qǐng)，格拉布斯受聘南方科技大學(xué)化學(xué)系學(xué)術(shù)顧問(wèn)委員會(huì)主席，并籌劃在南科大建立格拉布斯研究院，格拉布斯出任榮譽(yù)院長(zhǎng)，創(chuàng)始執(zhí)行院長(zhǎng)由張緒穆?lián)?。研究院以南方科技大學(xué)為依托，設(shè)置新醫(yī)藥研究中心、新材料研究中心、新能源研究中心，大力引進(jìn)全國(guó)乃至全世界的高端人才，在基礎(chǔ)研究領(lǐng)域進(jìn)行顛覆性原始創(chuàng)新，強(qiáng)力推動(dòng)深圳乃至中國(guó)在新醫(yī)藥、新材料和新能源等領(lǐng)域的基礎(chǔ)研究與產(chǎn)業(yè)發(fā)展。

為表彰他們?yōu)樯钲诎l(fā)展和國(guó)際交流合作所作出的巨大貢獻(xiàn)，6名來(lái)自各個(gè)領(lǐng)域的有識(shí)之士獲選為“2016時(shí)代深士”，張緒穆教授是教育界、科學(xué)界唯一入選者。源于他促成了格拉布斯與深圳的“聯(lián)姻”——深圳格拉布斯研究院在南方科技大學(xué)落地。何為“深士”？“諳政識(shí)商，照燭國(guó)際，集天下智慧，謀鵬城騰飛?！?/p>

“這份榮耀更加激發(fā)了我們回國(guó)創(chuàng)新創(chuàng)業(yè)的激情?！睆埦w穆說(shuō)。

“夏普萊斯和格拉布斯是詹姆斯·科爾曼（James P.Collman）教授20世紀(jì)70年代的弟子，我是90年代的弟子，當(dāng)年在他門(mén)下學(xué)習(xí)的時(shí)候，他也經(jīng)常囑咐我們，把兩位師兄作為榜樣?！睆埦w穆回憶說(shuō)。

“科爾曼是一代宗師，他今年已經(jīng)90歲了，我剛剛?cè)ニ固垢４髮W(xué)見(jiàn)了他。他對(duì)我目前的成就贊譽(yù)有加，對(duì)我寄予厚望?！闭劦綄?duì)導(dǎo)師印象最深刻的一句話，張緒穆回憶，“一個(gè)人學(xué)術(shù)的成就可能體現(xiàn)在文章上，但更重要的是體現(xiàn)在你培養(yǎng)的學(xué)生上。”科爾曼教授的話深深影響著張緒穆，“這些年來(lái)，我非常重視人才培養(yǎng)，正是在踐行導(dǎo)師的教誨。”

In recognition of their significant contributions to Shenzhen’s development and international exchange and cooperation, six insightful talents from various fields were selected as the “Shentlemen of the Year 2016”, and Prof.Zhang Xumu was the only one chosen from the education and science sectors, and this is because he facilitated the“marriage” between Grubbs and Shenzhen—the Shenzhen Grubbs Research Institute has landed on the ground in SUSTech. What is “Shentlemen”? “Understand politics and business; light up the international world; gather the world’s wisdom; seek general take-off.”

“This honor inspires us to return to China to innovate and start a new business.” Zhang Xumu said.

“Sharpless and Grubbs are the disciples of Prof. James P.Collman in the 1970s, and I was a disciple in the 1990s. When I studied under Prof. James P. Collman, he often instructed me to take the two elder brothers as role models.” Zhang Xumu recalled.

“Collman is a master of his generation. He is 90 years old now. I just went to Stanford University to meet him.He was very complimentary about my achievements and had high hopes for me.” Regarding the mentor’s words that impressed him most, Zhang Xumu recalled, “One’s academic achievements may be reflected in the articles, but more importantly in the students you cultivate.” Prof. Collman’s words profoundly influenced Zhang Xumu. “Over the years, I have attached great importance to talent cultivation,precisely practicing my mentor’s words.”

From chiral phenomenon to asymmetric catalysis

The chemical phenomenon behind the Thalidomide event that shocked the world in 1961 was the phenomenon of chirality.

Back then, an anti-pregnancy drug was widely used in Europe and Japan. It has two different structures, R and S.Just like our right and left hands, although they seem to be the same, they have other forms. The R-configuration of it is safe, while the S-configuration causes fetal malformations.It is as if it looks as similar as the right and left hands,while the right hand is good and the left hand is poisonous.However, the scientific community did not realize that the two conformations have different physiological activities in the human body. This oversight resulted in the heartbreaking fact of tens of thousands of “thalidomide babies,” i.e., the deformed newborns, in Europe and Japan. To obtain the desired results,asymmetric catalytic techniques were developed.

2023年5月28日，國(guó)際院士講堂第二期“中國(guó)健康醫(yī)藥產(chǎn)業(yè)化道路：不對(duì)稱(chēng)催化技術(shù)及在制藥工業(yè)中的應(yīng)用”嘉賓合影

從手性現(xiàn)象到不對(duì)稱(chēng)催化

1961年震驚世界的“反應(yīng)停事件”，背后隱藏的化學(xué)現(xiàn)象就是手性現(xiàn)象。

當(dāng)年，一種抗妊娠反應(yīng)藥物在歐洲和日本廣泛使用。它有R和S兩種不同結(jié)構(gòu)，就像我們的左右手，雖然看似一樣，但卻有著不同的結(jié)構(gòu)。其中的R構(gòu)形是安全的，而S構(gòu)形會(huì)導(dǎo)致胎兒畸形。好比說(shuō)看起來(lái)如左右手一般相似，右手是好的，左手卻是有毒的。但此前科學(xué)界沒(méi)有意識(shí)到兩種構(gòu)形在人體內(nèi)有不同的生理活性。而這一疏忽在歐洲和日本造成了數(shù)萬(wàn)“海豹兒”，也就是畸形新生兒，令人痛心疾首。為了獲得人們想要的結(jié)果，于是有了不對(duì)稱(chēng)催化技術(shù)。

作為一名科普愛(ài)好者，手性現(xiàn)象也成為采訪張?jiān)菏壳昂蠊P者最好奇的話題，為什么地球人的氨基酸都是左手手性，糖都是右手手性，在遙遠(yuǎn)的其他星球上，會(huì)不會(huì)有氨基酸的手性是和我們完全相反的存在？“手性的起源和人的起源一樣。人從哪里來(lái)，手性從哪里來(lái)？這個(gè)現(xiàn)象有很多假設(shè)。手性起源是《科學(xué)》雜志上的100個(gè)最具挑戰(zhàn)性的問(wèn)題之一，至今我們也不知道它怎么來(lái)的，誰(shuí)要是把手性起源搞清楚了，肯定也能拿諾貝爾獎(jiǎng)。”張緒穆笑著說(shuō)。

As a science enthusiast, the chiral phenomenon has also become the most curious topic of the interviewers: Why are all the amino acids of humanity left-handed chirality, and all the sugars right-handed chirality? Will there be the existence of amino acid chirality utterly opposite to ours on other distant planets “The origin of chirality is the same as the origin of man. Where does man come from, and where does chirality come from? There are many hypotheses for this phenomenon.The origin of chirality is one of the 100 most challenging questions inSciencejournals, and so far, we don’t know how it came about. Whoever determines the origin of chirality will also get a Nobel Prize.” Zhang Xumu said with a smile.

“How do you get a single chirality? It used to be measured.Both chirality exist, as if using a left or right glove, leaving the one you need and throwing away the other you don’t want. But that would waste half the material.” Zhang Xumu patiently explains, “Producing a single chirality can be controlled by a chiral ligand, like having a mold that directly turns a flat structure into the desired chiral structure. This is asymmetric catalysis, and asymmetric hydrogenation is the most effective.”

“Asymmetric hydrogenation is essential for efficiently synthesizing chiral APIs and their intermediates. More than60% of small molecule drugs are chiral, of which 60% can be obtained by asymmetric hydrogenation.” Zhang Xumu said.

“怎么獲得單一手性？以前是測(cè)分，這兩種手性都有，好比用一只左手或者右手的手套，把需要的留下，另一種不要的扔掉。不過(guò)這就會(huì)浪費(fèi)掉一半的材料。”張緒穆耐心地解釋?zhuān)吧a(chǎn)單一手性可以靠手性配體來(lái)控制，這好比有一個(gè)模子，直接把平面的結(jié)構(gòu)變成想要的手性結(jié)構(gòu)，這就是不對(duì)稱(chēng)催化，而不對(duì)稱(chēng)氫化是其中最有效的。”

“不對(duì)稱(chēng)氫化對(duì)于手性原料藥及其中間體的高效合成至關(guān)重要。小分子藥物60%以上為手性藥物，其中60%可以通過(guò)不對(duì)稱(chēng)氫化得到?！睆埦w穆說(shuō)。

張緒穆在不對(duì)稱(chēng)氫化和手性膦配體研究領(lǐng)域取得了豐碩的研究成果。他開(kāi)發(fā)的手性工具箱廣泛應(yīng)用于不對(duì)稱(chēng)氫化、不對(duì)稱(chēng)氫甲?；磻?yīng)等領(lǐng)域，具有重要的國(guó)際影響力，因此他成為榮獲美國(guó)化學(xué)會(huì)亞瑟·科普學(xué)者獎(jiǎng)（Arthur C.Cope Scholar Awards）的首位來(lái)自中國(guó)大陸的學(xué)者。

“2000年前后我提出3S概念，反應(yīng)要快（Speed），選擇性（Selectivity）好，還有一個(gè)是催化劑穩(wěn)定性（Stability）好，有自主知識(shí)產(chǎn)權(quán)，能達(dá)到百萬(wàn)轉(zhuǎn)化數(shù)，甚至千萬(wàn)轉(zhuǎn)化數(shù)，是我們追求的目標(biāo)。”張緒穆說(shuō)。

他開(kāi)發(fā)的張烯炔環(huán)異構(gòu)化反應(yīng)，是以華人學(xué)者命名的少數(shù)人名反應(yīng)之一，對(duì)藥物綠色合成產(chǎn)生了重大影響。據(jù)了解，全世界人名反應(yīng)有200個(gè)左右，華人人名反應(yīng)在各種教科書(shū)中有5個(gè)左右。

“教科書(shū)當(dāng)中的人名反應(yīng)，就像數(shù)學(xué)的定理一樣，這是我們科學(xué)家得到公認(rèn)之后的一個(gè)榮耀。終于有一個(gè)以我的名字來(lái)命名的國(guó)際公認(rèn)的反應(yīng)了。”張緒穆分享當(dāng)時(shí)的心情，他笑言：“當(dāng)然我還想有第二個(gè)?！被趲熜窒钠杖R斯“大道至簡(jiǎn)”的啟發(fā)，張緒穆將自己最新的不對(duì)稱(chēng)催化科研成果凝結(jié)成一個(gè)名稱(chēng)“@Catalysis”，也就是“@催化”。筆者期待與讀者們一起，見(jiàn)證“@催化”的成熟、推廣與豐碩的成就。

Zhang Xumu has achieved fruitful research results in asymmetric hydrogenation and chiral phosphine ligand research. The chiral toolbox he developed is widely used in asymmetric hydrogenation and asymmetric hydroformylation reactions, which has a significant international influence. Thus, he became the first scholar from Chinese mainland to win the Arthur C. Cope Scholar Awards of the American Chemical Society.

“Around 2000, I put forward the 3S concept: high“Speed” of reaction, good “Selectivity,” good “Stability”of catalyst. We pursue owning independent intellectual property rights and reaching millions or even ten million conversions.” Zhang Xumu said.

The Zhang Enyne Cycloisomerization that he developed is one of the few human-named reactions named after Chinese scholars and has significantly impacted the green synthesis of drugs. It is known that there are about 200 human-named reactions around the world, and there are about five Chinese human-named reactions in various textbooks.

“Like a theorem in mathematics, a reaction named after a person’s name in the textbooks is an honor for scientists once we are recognized. Finally, there is an internationally recognized reaction named after me.” Sharing his feelings at the time, Zhang Xumu laughed, “Of course I want a second one.” Based on the inspiration of Sharpless’s “greatest truths always turn out to be simple”, Zhang Xumu condensed his latest asymmetric catalytic achievements into a single name,“@Catalysis.” It is worth looking forward to witnessing the maturity, popularization, and fruitful achievements of “@Catalysis.”

International peers have highly evaluated his research results: Mr. Zhang’s research on chiral ligands for asymmetric hydrogenation is an essential step toward practical asymmetric catalysis. His development of catalysts for the highly enantioselective hydrogenation of fatty ketones has impacted the asymmetric hydrogenation of simple ketones comparable to that of Ryoji Noyori, the 2001 Nobel Laureate in Chemistry.

Scientist entrepreneurship: On bookshelves as well as goods shelves

In 1999, Zhang Xumu went to the laboratories of two Nobel Prize winners, his senior fellow apprentices,for academic vacations. There, he found that they paid particular attention to the practical value of academics,which inspired Zhang Xumu a lot. So, Zhang Xumu started his path of “Scientist Entrepreneurship”.

國(guó)際同行高度評(píng)價(jià)了他的研究成果：張先生用于不對(duì)稱(chēng)氫化的手性配體研究，向?qū)嵱玫牟粚?duì)稱(chēng)催化邁出了重要的一步。他發(fā)展的用于高對(duì)映選擇性地氫化脂肪酮的催化劑，在簡(jiǎn)單酮的不對(duì)稱(chēng)氫化方面的影響力，與2001年諾貝爾化學(xué)獎(jiǎng)獲得者野依良治（Ryoji Noyori）不相上下。

科學(xué)家創(chuàng)業(yè)：書(shū)架貨架都要上

1999年，張緒穆去兩位諾貝爾獎(jiǎng)獲得者兼同門(mén)師兄的實(shí)驗(yàn)室進(jìn)行學(xué)術(shù)休假，發(fā)現(xiàn)師兄們對(duì)學(xué)術(shù)的實(shí)踐價(jià)值特別重視，這給了張緒穆很大啟發(fā)，于是張緒穆開(kāi)啟了自己的“科學(xué)家企業(yè)創(chuàng)始人”之路。

張緒穆分享說(shuō)：“其一，辦公司更有利于自己做一些化學(xué)基本原理的創(chuàng)新；其次，在高校里，用我們的聰明才智創(chuàng)造新物質(zhì)，這可以算是上了書(shū)架，而如果形成的產(chǎn)品能夠轉(zhuǎn)化，那就算上了貨架；最后，還有一個(gè)很重要的是培養(yǎng)人才，培養(yǎng)產(chǎn)學(xué)結(jié)合的人才?！睆埦w穆認(rèn)為，一流大學(xué)并不是關(guān)起門(mén)來(lái)做學(xué)術(shù)，做出來(lái)的成果不僅能放在書(shū)架上，還能放在貨架上，展示科學(xué)研究的社會(huì)效益，為社會(huì)和人類(lèi)創(chuàng)造價(jià)值。他長(zhǎng)期致力于發(fā)展高效、高選擇性不對(duì)稱(chēng)催化反應(yīng)，利用自己原創(chuàng)的手性配體工具箱為技術(shù)平臺(tái)，以重大藥物合成為產(chǎn)業(yè)化突破口，開(kāi)發(fā)有自主知識(shí)產(chǎn)權(quán)、安全、環(huán)保、低成本、高質(zhì)量的藥物綠色合成新工藝。他先后成立了凱瑞斯德生化（蘇州）有限公司（以下簡(jiǎn)稱(chēng)凱瑞斯德）、凱特立斯深圳科技有限公司（以下簡(jiǎn)稱(chēng)凱特立斯）和深圳安泰維生物醫(yī)藥有限公司（以下簡(jiǎn)稱(chēng)安泰維）三家公司。

2023年5月28日，張緒穆在國(guó)際院士講堂進(jìn)行主題分享

Zhang Xumu shared, “Firstly, running a company is more conducive to doing some innovation in the basic chemistry principles. Secondly, in the university, using our ingenuity to create something new can be considered to be on the bookshelves. However, if the products can be transformed, they will be considered on the goods shelves.Lastly, it is important to cultivate talents who integrate production and learning.” Zhang Xumu believes that the first-class university makes achievements that should not only be put on the bookshelves but also on the goods shelves,rather than academics indoors, so that it benefits scientific research and creates value for society and humanity. He has long been committed to the development of efficient and highly selective asymmetric catalytic reactions, using his original chiral ligand toolbox as a technology platform,taking major drug synthesis as an industrialization breakthrough, and developing new processes for green synthesis of drugs with independent intellectual property rights, safe, environmentally friendly, low-cost and high quality. He has successively established three companies,namely “Chiral Quest (Suzhou) Co., Ltd. (from now on referred to as ‘Chiral Quest’),” “Kaitelis (Shenzhen)Technology Co., Ltd. (from now on ‘Catalyst Technology’),”and “Shenzhen Antiv Pharma Co., Ltd. (from now on as‘Antiv’).”

Founded in 2008, Chiral Quest has already produced more than 20 new process routes with an annual production capacity of more than 5 tons. It makes hundreds of tons of pharmaceutical intermediates and APIs yearly related to the medication needs of hundreds of millions of patients worldwide. “Chiral Quest is the first company I founded,gathering my years of scientific research. We have an R&D headquarters in Suzhou, a production base in Jiangxi, and sales offices in the UK and India. We look forward to listing on the Sci-Tech Innovation Board shortly.” Zhang Xumu said.

凱瑞斯德成立于2008年，已有20多個(gè)年產(chǎn)大于5噸的新工藝路線投入生產(chǎn)，每年生產(chǎn)幾百?lài)嶀t(yī)藥中間體和原料藥，關(guān)乎全世界數(shù)億患者的用藥需求?！皠P瑞斯德是我成立的第一家公司，聚集了我多年的科研成果。蘇州有研發(fā)總部，江西有生產(chǎn)基地。我們?cè)谟?guó)、印度都有銷(xiāo)售辦公室，期待在不久的將來(lái)在科創(chuàng)板上市?！睆埦w穆說(shuō)。

2015年，以張緒穆為主導(dǎo)的團(tuán)隊(duì)獲批深圳市海外高層次人才“孔雀團(tuán)隊(duì)”，成立凱特立斯，并于2018年正式啟動(dòng)項(xiàng)目研發(fā)，目前已取得沙庫(kù)必曲、尼古丁、西那卡塞、苯福林、依折麥布、孟魯斯特等10多種大品種藥物新工藝路線的重大突破?！皠P特立斯是一個(gè)平臺(tái)公司，輕資產(chǎn)模式，賦能產(chǎn)業(yè)?！睆埦w穆解釋說(shuō)。

至于2021年創(chuàng)立的抗病毒新藥公司安泰維，“這家公司在我看來(lái)是我們孵化的跨界新星。”張緒穆說(shuō)。

“頂天立地、國(guó)家需求、原始創(chuàng)新”是這位科學(xué)家創(chuàng)始人一以貫之的指導(dǎo)思想?！拔覀円嫦蚴澜缈茖W(xué)前沿、面向經(jīng)濟(jì)主戰(zhàn)場(chǎng)、面向國(guó)家重大需求、面向人民生命健康，頂天立地，國(guó)家需求，原始創(chuàng)新?！睆埦w穆說(shuō)，他尤其強(qiáng)調(diào)原始創(chuàng)新?！爸挥性紕?chuàng)新才是‘卡住脖子’的，你要是跟在別人后面亦步亦趨，你始終在給別人抬轎子。”原始創(chuàng)新也就是羅伯特·蘭格原則中的專(zhuān)利。

張緒穆（右一）與2001年、2022年諾貝爾化學(xué)獎(jiǎng)獲得者巴里·夏普萊斯（K.Barry Sharpless）（中）合照

除了師兄的影響，張緒穆的科學(xué)家創(chuàng)業(yè)理念也受到麻省理工學(xué)院著名科學(xué)家與企業(yè)家羅伯特·蘭格（Robert Langer）的影響。采訪中，張緒穆分享了羅伯特·蘭格的“3個(gè)P”原則也就是平臺(tái)（Platform）、學(xué)術(shù)文章（Paper）、專(zhuān)利（Patent），“再加上良好的創(chuàng)新生態(tài)，才能讓科學(xué)家的研究成果加快向市場(chǎng)轉(zhuǎn)化?！?/p>

In 2015, the team led by Zhang Xumu was approved by Shenzhen’s “Peacock Team” of overseas high-level talents,and kaitelis was set up. It formally launched the project research and development in 2018 and has made a significant breakthrough in the new process of more than ten large varieties of drugs, such as sakubitril, nicotine, cinacalcet,benfotiamine, ezetimibe, and mengluste. “kaitelis is a platform company with an asset-light model to empower the industry.” Zhang Xumu explained.

As for Antiv, a new antiviral drug company founded in 2021, “This company is a cross and a rising star that we have incubated, I think.” Zhang Xumu said.

“An indomitable spirit, national needs, original innovation” is the consistent guiding principle of this scientist entrepreneur. “We have to face the world’s scientific frontiers, face the main battlefield of the economy, face the country’s major needs, and face the people’s life and health.We should pursue an indomitable spirit, national needs, and original innovation.” Zhang Xumu said that he particularly emphasized original innovation. “Only the original innovation is the bottleneck. If you always follow others,you do a hard but resultless job.” Original innovation is also known as patents in Robert Langer’s principles.

新冠口服藥“SHEN26”正在進(jìn)行時(shí)

“目前我們正在進(jìn)行新型冠狀病毒小分子口服藥SHEN26的臨床研究，已在全國(guó)20多個(gè)中心開(kāi)展Ⅲ期臨床試驗(yàn)，并在繼續(xù)新增臨床試驗(yàn)中心的受試者入組，進(jìn)展順利。期待今年內(nèi)能上市?！睆埦w穆說(shuō)。

2020年年初新冠疫情暴發(fā)以后，張緒穆攜團(tuán)隊(duì)與中山大學(xué)郭德銀教授團(tuán)隊(duì)開(kāi)發(fā)抗新冠口服藥物，化合物“SHEN26”是科技部新冠專(zhuān)項(xiàng)資助的五個(gè)小分子抗新冠藥物中的一個(gè)。

張緒穆介紹說(shuō)，SHEN26膠囊是一款廣譜的RNA依賴(lài)性RNA聚合酶（RdRp）抑制劑，實(shí)驗(yàn)室數(shù)據(jù)和相關(guān)的研究結(jié)果顯示，RdRp靶點(diǎn)具有廣譜性，對(duì)不同新冠病毒變異株均有高效的體外抑制活性，并且具有拓展RSV病毒適應(yīng)證的潛力。SHEN26膠囊已完成的Ⅱ期臨床研究結(jié)果顯示，與安慰劑組對(duì)比，服用SHEN26膠囊后，患者體內(nèi)的病毒載量下降趨勢(shì)明顯，安全性表現(xiàn)優(yōu)異。SHEN26膠囊分子式結(jié)構(gòu)設(shè)計(jì)科學(xué)合理、生產(chǎn)工藝成熟高效，有助于降低用藥成本，提升患者用藥可及性。據(jù)了解，SHEN26膠囊更為合理的設(shè)計(jì)與更為成熟高效的工藝所帶來(lái)的成本優(yōu)勢(shì)，不僅有望為更廣大的患者用藥提供便利，也將為公司的產(chǎn)品定價(jià)帶來(lái)更大的空間。

最新公告披露，在國(guó)內(nèi)眾多在研新冠口服藥中，目前安泰維與科興制藥全資子公司深圳科興藥業(yè)有限公司合作開(kāi)發(fā)的SHEN26膠囊研發(fā)進(jìn)度已跑在前列。隨著Ⅲ期臨床試驗(yàn)的順利開(kāi)展，待SHEN26膠囊上市后有望憑借良好的臨床效果、安全性以及成本優(yōu)勢(shì)打開(kāi)市場(chǎng)，在實(shí)現(xiàn)業(yè)績(jī)表現(xiàn)的同時(shí)，為廣大百姓對(duì)抗新冠病毒帶來(lái)更優(yōu)的選擇。

In addition to the influence of his senior, Zhang Xumu’s entrepreneurial philosophy as a scientist was also influenced by Robert Langer, a renowned scientist and entrepreneur at the Massachusetts Institute of Technology(MIT). In the interview, Zhang Xumu shared Robert Langer’s 3P principles, representing Platform, Paper and Patent. “Only with a good innovation ecosystem can it accelerate the transformation of scientists’ research results towards the market.”

COVID-19 oral medicine in progress

“We are currently conducting clinical studies of SHEN26. It has been conducting Phase III clinical trials at more than 20 centers nationwide and is continuing to enroll subjects at additional clinical trial centers. It progresses well. It is expected to be on the market within this year.” Zhang Xumu said.

After the outbreak of COVID-19 in early 2020, Zhang Xumu and Professor Guo Deyin’s team at Sun Yat-sen University developed anti-COVID-19 oral medicine. The compound “SHEN26” is one of the five small-molecule anti-COVID-19 medicines the Ministry of Science and Technology funds.

Zhang Xumu said that the SHEN26 capsule is a broadspectrum RNA-dependent RdRp inhibitor. Laboratory data and research results show that the RdRp target has a broad spectrum, with high affection in vitro inhibitory activity against different COVID-19 variants. It also has the potential to expand the indications of the RSV virus.SHEN26 capsule has completed Phase II clinical study,and the results show that compared with the placebo group, the viral load in the body of the patients who take SHEN26 capsules decreases significantly, and the safety performance is excellent. The molecular structure design of the SHEN26 capsule is scientific and reasonable, and the production process is mature and efficient, which can help reduce the cost of medication and enhance the accessibility to patients. It is understood that the more reasonable design and more mature and efficient process of cost advantages of the SHEN26 capsule is expected to provide convenience for a broader range of patients and the company’s product pricing.

The latest announcement showed that, among the many anti-COVID-19 oral medicines under development in China, the R&D progress of the SHEN26 capsule, which is jointly developed by Antiv and the branch of Shenzhen Sinovac, has ranked first. With the smooth development of phase III clinical trials, SHEN26 capsule is expected to open up the market with good clinical results, safety, and cost advantages. Harvesting good performance brings better choices for the general public to fight against the COVID-19 virus.

“解決科學(xué)難題，同時(shí)造福人類(lèi)”

張緒穆認(rèn)為，更多中國(guó)科學(xué)家獲得諾獎(jiǎng)，這是一個(gè)時(shí)間問(wèn)題?！爸皇沁t早的事，一般來(lái)說(shuō)，諾獎(jiǎng)是認(rèn)可科學(xué)家差不多20年前的工作。中國(guó)真正發(fā)力在科技創(chuàng)新也就是現(xiàn)在，20年之后我相信會(huì)有更多中國(guó)科學(xué)家拿諾獎(jiǎng)?！?/p>

筆者問(wèn)及對(duì)年輕學(xué)者的建議，張緒穆說(shuō)：“一定要有開(kāi)創(chuàng)一個(gè)領(lǐng)域的磅礴大氣，擁有一棵樹(shù)比在樹(shù)上剪一些枝枝葉葉要好。創(chuàng)造力比知識(shí)更重要，保持對(duì)科學(xué)的洞察力，盡快找到自己感興趣又有能力的方向，獨(dú)樹(shù)一幟，開(kāi)創(chuàng)未來(lái)，從0到1，持之以恒。”

“解決科學(xué)難題，同時(shí)造福人類(lèi)。”這句話源自張緒穆對(duì)巴斯德象限的思考。曾經(jīng)有一個(gè)學(xué)生問(wèn)他，怎樣才能成為頂級(jí)科學(xué)家。他拿出一張還畫(huà)有幾個(gè)分子結(jié)構(gòu)的紙，畫(huà)了一個(gè)直角坐標(biāo)系，說(shuō)：“橫坐標(biāo)是學(xué)術(shù)本身，一個(gè)精妙的反應(yīng)、一個(gè)復(fù)雜數(shù)學(xué)模型的建立、一個(gè)艱難實(shí)驗(yàn)的完成都可以讓我們站在這個(gè)坐標(biāo)的最右端；縱坐標(biāo)是它的實(shí)踐價(jià)值，一個(gè)能救治病人的特效藥、一個(gè)能增加糧食產(chǎn)量的新方法都可以使我們處于這個(gè)坐標(biāo)的最上端。然而有些極難的科學(xué)問(wèn)題并不能被廣泛應(yīng)用，而有些改變?nèi)藗兩罘绞降陌l(fā)明，其實(shí)又不需要太多的高科技?！苯又霉P重重地點(diǎn)在了坐標(biāo)系的右上角，說(shuō)道，“那些同時(shí)解決了科技難題又造福人類(lèi)的才是最頂尖的科學(xué)家?！?/p>

“我鼓勵(lì)我的學(xué)生繼續(xù)做這個(gè)事情。如果說(shuō)珠穆朗瑪峰是我們要攀登的最高峰，還沒(méi)到頂，我們還要再繼續(xù)努力，世上無(wú)難事，只要肯登攀，我們還得往前走?！睆埦w穆說(shuō)。

而他名字當(dāng)中的“穆”，正是珠穆朗瑪峰的“穆”。

“Solving scientific problems while benefiting mankind”

Zhang Xumu believes that more Chinese scientists will win the Nobel Prize sooner or later. “It’s just a matter of time. Generally speaking, the Nobel Prize is to recognize the work of scientists almost 20 years ago. Now, it is the shot of China’s real science and technology innovation power. After 20 years, I believe there will be more Chinese scientists to take the Nobel Prize.”

The author asked about the advice for young scholars,and Zhang Xumu said, “Young scholars must have the majesty of pioneering. Planting a tree is better than pruning branches and leaves. Creativity is more important than knowledge. Keep the insight of science. Find what they are interested in and good at as soon as possible. Be unique and adhere to pioneering the future from 0 to 1.”

“Solving scientific problems while benefiting mankind.” This sentence originated from Zhang Xumu’s reflection on Pasteur’s quadrant. A student once asked him how to become a top scientist. He took out a piece of paper with a few molecular structures still drawn,drew a right-angle coordinate system, and said, “The horizontal coordinate is the academics itself. A subtle reaction, establishing a complex mathematical model, and completing a difficult experiment can make us stand at the rightmost end of this coordinate. The vertical coordinate is its practical value. A potent medicine that can save a life and a new method that can increase food production can put us at the top of this coordinate. Yet, some challenging scientific problems cannot be widely applied. While some inventions change people’s lifestyle, they don’t require much high technology.” Then, with a heavy point of his pen in the upper right corner of the coordinate system, he said, “Those who simultaneously solve scientific problems and benefit mankind are the top scientists.”

“I encourage my students to keep exploring. If Mount Qomolangma is the highest peak we have to climb, we haven’t reached the top yet. We have to continue to work harder. Nothing is difficult in the world as long as we are willing to go all out. We still have to forge ahead.” Zhang Xumu said.

What’s more, the “Mu” in his name is precisely the“Mu” in “Zhu Mu Lang Ma”(translated name of Mount Qomolangma).