{"id":25580,"date":"2020-01-30T11:14:03","date_gmt":"2020-01-30T19:14:03","guid":{"rendered":"https:\/\/vermont.salk.edu\/?post_type=disclosure&p=25580"},"modified":"2024-01-30T14:42:25","modified_gmt":"2024-01-30T22:42:25","slug":"imaging-study-of-key-viral-structure-shows-how-hiv-drugs-work-at-atomic-level","status":"publish","type":"disclosure","link":"https:\/\/www.salk.edu\/zh\/news-release\/imaging-study-of-key-viral-structure-shows-how-hiv-drugs-work-at-atomic-level\/","title":{"rendered":"\u5bf9\u5173\u952e\u75c5\u6bd2\u7ed3\u6784\u7684\u6210\u50cf\u7814\u7a76\u663e\u793a\u4e86\u827e\u6ecb\u75c5\u75c5\u6bd2\u836f\u7269\u5728\u539f\u5b50\u5c42\u9762\u7684\u4f5c\u7528\u673a\u5236"},"content":{"rendered":"

LA JOLLA\u2014Salk scientists have discovered how a powerful class of HIV drugs binds to a key piece of HIV machinery. By solving, for the first time, three-dimensional structures of this complex while different drugs were attached, the researchers showed what makes the therapy so potent. The work, which appeared in \u79d1\u5b66<\/em><\/a> on January 30, 2020, provides insights that could help design or improve new treatments for HIV.<\/p>\n

\u201cThe drugs we studied are the latest compounds available in the clinic today, as well as several important pre-clinical molecules. Until now, no one knew exactly how they bound to this HIV complex,\u201d says the study\u2019s senior author\u00a0Dmitry Lyumkis<\/a>, an assistant professor in Salk\u2019s Laboratory of Genetics. \u201cA better understanding of how the drugs work will help us improve them and design new therapeutic compounds.\u201d<\/p>\n

\"This
This illustration depicts the molecular structure of an HIV drug (at center) bound to an active site of the HIV intasome (surrounding structure), the viral machine that allows HIV to infect human immune cells. By filling the binding pocket, the drug blocks the normal function of the machine, thereby preventing the virus from establishing an infection in the target cell.<\/p>\n

Click here<\/a> for a high-resolution image.<\/p>\n

Credit: Salk Institute<\/figcaption><\/figure>\n

The intasome is a crucial structure of the virus that enables infection, composed of the HIV protein integrase and strands of viral DNA that form when the virus enters human cells. The intasome moves into each human cell and then carries out the chemical reactions necessary to integrate the virus\u2019 genetic material into human DNA.<\/p>\n

Some drugs, called integrase strand transfer inhibitors (INSTIs), have managed to block the intasome; HIV can\u2019t infect human cells when the complex can\u2019t integrate viral DNA into the human genome. There are currently four INSTIs approved by the US Food and Drug Administration, as well as others under development.<\/p>\n

Despite the success of these molecules, researchers have struggled to study how they inhibit the HIV intasome, largely due to difficulty in isolating intasomes for structural studies. In the past, most research on the intasome and INSTIs was carried out on another retrovirus called prototype foamy virus, or PFV. In 2017, Lyumkis and his colleagues were the first to determine the structure of purified HIV intasomes<\/a>.<\/p>\n

In the new work, Lyumkis\u2019 team went a step further: they obtained the structure of HIV intasomes while they were being actively blocked by one of four INSTIs\u2014the commercially available drug bictegravir or three experimental compounds known as 4f, 4d and 4c. The team used tilted single-particle cryo-electron microscopy (cryo-EM), an imaging technique they\u2019ve helped optimize<\/a>, to reveal the structure of each intasome-drug complex.<\/p>\n

The first observation that Lyumkis made was just how differently the drugs attached to the HIV intasome than what had been seen with the PFV intasome. The compound known as 4f, for instance, loops backwards onto itself as it binds to the PFV intasome but remains relatively flat as it attaches to the HIV version of the complex, details which can help researchers improve the binding properties of potential future molecules.<\/p>\n

\u201cTo this day, everyone is still using the PFV intasome structure to rationalize and understand the mechanism of action of these drugs,\u201d says Dario Passos, the study\u2019s co-first author and a staff scientist in Lyumkis\u2019 laboratory. \u201cBut we\u2019ve shown that the field really needs to move and study the HIV structure if we want to make further progress.\u201d<\/p>\n

\"From
From left: Dario Oliveira Passos, Dmitry Lyumkis and Ilona K. Jo\u0301z\u0301wik<\/p>\n

Click here<\/a> for a high-resolution image<\/p>\n

Credit: Salk Institute<\/figcaption><\/figure>\n

\u201cWe and many others have been working towards this goal for several decades and it is exciting that at long last we can now understand how HIV inhibitors work in detail and aid the development of new drugs.\u201d says Min Li, co-first author and a staff scientist at the National Institute of Diabetes and Digestive and Kidney Diseases.<\/p>\n

The structures also revealed why the drugs are so potent and what makes them so good at avoiding drug resistance. The INSTIs, Lyumkis and his colleagues found, fill the entire space that\u2019s normally occupied by DNA.\u00a0 That means if the HIV intasome develops a mutation that blocks the INSTI drugs from binding, it also blocks the DNA from attaching, rendering the complex useless for invading human cells.<\/p>\n

Finally, the extremely high resolution of the structure obtained by the Salk researchers lets them see details on how the drugs chemically interacted with this binding pocket, and how INSTIs displaced water molecules to do so, which gave the team even more information on what makes INSTIs so successful in the clinic.<\/p>\n

\u201cIn previous structures, we learned about intasome biology,\u201d says Lyumkis. \u201cBut here, we\u2019ve really started to gain insight into the therapeutic angle of how drugs can target these important viral assemblies.\u201d<\/p>\n

The researchers are planning additional work on the experimental drugs\u2014focusing on the compound known as 4d, which, based on both preclinical testing and the new structural insight, shows more promise against HIV than other compounds. They also want to better understand what happens to the structure of the intasome in cases where it develops resistance to INSTIs. This could help them design more efficient drugs in the future, says Lyumkis.<\/p>\n

Other researchers on the study were Ilona J\u00f3\u017awik and Youngmin Jeon of Salk; Renbin Yang and Robert Craigie of the National Institute of Diabetes and Digestive Diseases; Xue Zhi Zhao, Steven Smith, Stephen Hughes and Terrence Burke Jr. of the National Cancer Institute; and Diogo Santos-Martins and Stefano Forli of The Scripps Research Institute.<\/p>\n

The work and the researchers involved were supported by grants from the National Institutes of Health, the Intramural Programs of the National Institute of Diabetes and Digestive Diseases, the Intramural Programs of the National Cancer Institute, and the Intramural AIDS Targeted Anti-Viral Program of the National Institutes of Health.<\/p>","protected":false},"featured_media":25585,"template":"","faculty":[320],"disease-research":[457,122,366],"class_list":["post-25580","disclosure","type-disclosure","status-publish","has-post-thumbnail","hentry","faculty-dmitry-lyumkis","disease-research-hiv","disease-research-immune-system-biology","disease-research-infectious-disease"],"acf":[],"yoast_head":"\nImaging study of key viral structure shows how HIV drugs work at atomic level - Salk Institute for Biological Studies<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.salk.edu\/zh\/news-release\/imaging-study-of-key-viral-structure-shows-how-hiv-drugs-work-at-atomic-level\/\" \/>\n<meta property=\"og:locale\" content=\"zh_CN\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Imaging study of key viral structure shows how HIV drugs work at atomic level - Salk Institute for Biological Studies\" \/>\n<meta property=\"og:description\" content=\"LA JOLLA\u2014Salk scientists have discovered how a powerful class of HIV drugs binds to a key piece of HIV machinery. 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