Bringing Needed Structure to COVID-19 Drug Development

Posted on April 2nd, 2020 by Dr. Francis Collins

SARS-Cov-2 Molecular Map — Caption: Molecular map showing interaction between the spike protein (gold) of the novel coronavirus and the peptidase domain (blue) of human angiotensin-converting enzyme 2 (ACE2). Credit: Adapted from Yan R., Science, 2020.

With so much information swirling around these days about the coronavirus disease 2019 (COVID-19) pandemic, it would be easy to miss one of the most interesting and significant basic science reports of the past few weeks. It’s a paper published in the journal Science [1] that presents an atomic-scale snapshot showing the 3D structure of the spike protein on the novel coronavirus attached to a human cell surface protein called ACE2, or angiotensin converting enzyme 2. ACE2 is the receptor that the virus uses to gain entry.

What makes this image such a big deal is that it shows—in exquisite detail—how the coronavirus attaches to human cells before infecting them and making people sick. The structural map of this interaction will help guide drug developers, atom by atom, in devising safe and effective ways to treat COVID-19.

This new work, conducted by a team led by Qiang Zhou, Westlake Institute for Advanced Study, Hangzhou, China, took advantage of a high-resolution imaging tool called cryo-electron microscopy (cryo-EM). This approach involves flash-freezing molecules in liquid nitrogen and bombarding them with electrons to capture their images with a special camera. When all goes well, cryo-EM can solve the structure of intricate macromolecular complexes in a matter of days, including this one showing the interaction between a viral protein and human protein.

Zhou’s team began by mapping the structure of human ACE2 in a complex with B0AT1, which is a membrane protein that it helps to fold. In the context of this complex, ACE2 is a dimer—a scientific term for a compound composed of two very similar units. Additional mapping revealed how the surface protein of the novel coronavirus interacts with ACE2, indicating how the virus’s two trimeric (3-unit) spike proteins might bind to an ACE2 dimer. After confirmation by further research, these maps may well provide a basis for the design and development of therapeutics that specifically target this critical interaction.

The ACE2 protein resides on the surface of cells in many parts of the human body, including the heart and lungs. The protein is known to play a prominent role in the body’s complex system of regulating blood pressure. In fact, a class of drugs that inhibit ACE and related proteins are frequently prescribed to help control high blood pressure, or hypertension. These ACE inhibitors lower blood pressure by causing blood vessels to relax.

Since the COVID-19 outbreak, many people have wondered whether taking ACE inhibitors would be helpful or detrimental against coronavirus infection. This is of particular concern to doctors whose patients are already taking the medications to control hypertension. Indeed, data from China and elsewhere indicate hypertension is one of several coexisting conditions that have consistently been reported to be more common among people with COVID-19 who develop life-threatening severe acute respiratory syndrome.

In a new report in this week’s New England Journal of Medicine, a team of U.K. and U.S. researchers, partly supported by NIH, examined the use of ACE inhibitors and other angiotensin-receptor blockers (ARBs) in people with COVID-19. The team, led by Scott D. Solomon of Brigham and Women’s Hospital and Harvard Medical School, Boston, found that current evidence in humans is insufficient to support or refute claims that ACE inhibitors or ARBs may be helpful or harmful to individuals with COVID-19.

The researchers concluded that these anti-hypertensive drugs should be continued in people who have or at-risk for COVID-19, stating: “Although additional data may further inform the treatment of high-risk patients … clinicians need to be cognizant of the unintended consequences of prematurely discontinuing proven therapies in response to hypothetical concerns.” [2]

Research is underway to generate needed data on the use of ACE inhibitors and similar drugs in the context of the COVID-19 pandemic, as well as to understand more about the basic mechanisms underlying this rapidly spreading viral disease. This kind of fundamental research isn’t necessarily the stuff that will make headlines, but it likely will prove vital to guiding the design of effective drugs that can help bring this serious global health crisis under control.

References:

[1] Structural basis for the recognition of the SARS-CoV-2 by full-length human ACE2 . Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Science. 27 March 2020. [Epub ahead of publication]

[2] Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. Vaduganathan M, Vardeny O, Michel T, McMurray J, Pfeffer MA, Solomon SD. 30 NEJM. March 2020 [Epub ahead of Publication]

Links:

Coronavirus (COVID-19) (NIH)

COVID-19, MERS & SARS (National Institute of Allergy and Infectious Diseases/NIH)

Transformative High Resolution Cryo-Electron Microscopy (Common Fund/NIH)

Qiang Zhou (Westlake Institute for Advanced Study, Zhejiang Province)

Scott D. Solomon (Brigham and Women’s Hospital, Boston)

NIH Support: National Center for Advancing Translational Sciences; National Heart, Lung, and Blood Institute