Study identifies 21 existing drugs that could treat COVID-19
Multiple drugs improve the activity of remdesivir, a current standard-of-
care treatment for COVID-19

Date:
July 24, 2020
Source:
Sanford Burnham Prebys Medical Discovery Institute
Summary:
A new study has identified 21 existing drugs that stop the
replication of SARS-CoV-2, the virus that causes COVID-19.



FULL STORY ==========================================================================
A Nature study authored by a global team of scientists and led by Sumit
Chanda, Ph.D., professor at Sanford Burnham Prebys Medical Discovery
Institute, has identified 21 existing drugs that stop the replication
of SARS-CoV-2, the virus that causes COVID-19.


==========================================================================
The scientists analyzed one of the world's largest collections of
known drugs for their ability to block the replication of SARS-CoV-2,
and reported 100 molecules with confirmed antiviral activity in
laboratory tests. Of these, 21 drugs were determined to be effective at concentrations that could be safely achieved in patients. Notably, four
of these compounds were found to work synergistically with remdesivir,
a current standard-of-care treatment for COVID-19.

"Remdesivir has proven successful at shortening the recovery time for
patients in the hospital, but the drug doesn't work for everyone who
receives it. That's not good enough," says Chanda, director of the
Immunity and Pathogenesis Program at Sanford Burnham Prebys and senior
author of the study. "As infection rates continue to rise in America
and around the world, the urgency remains to find affordable, effective,
and readily available drugs that can complement the use of remdesivir, as
well as drugs that could be given prophylactically or at the first sign
of infection on an outpatient basis." Extensive testing conducted In
the study, the research team performed extensive testing and validation studies, including evaluating the drugs on human lung biopsies that
were infected with the virus, evaluating the drugs for synergies with remdesivir, and establishing dose-response relationships between the
drugs and antiviral activity.

Of the 21 drugs that were effective at blocking viral replication,
the scientists found:
* 13 have previously entered clinical trials for other indications
and are
effective at concentrations, or doses, that could potentially be
safely achieved in COVID-19 patients.

* Two are already FDA approved: astemizole (allergies), clofazamine
(leprosy), and remdesivir has received Emergency Use Authorization
from the agency (COVID-19).

* Four worked synergistically with remdesivir, including the
chloroquine
derivative hanfangchin A (tetrandrine), an antimalarial drug that
has reached Phase 3 clinical trials.

"This study significantly expands the possible therapeutic options for
COVID-19 patients, especially since many of the molecules already have
clinical safety data in humans," says Chanda. "This report provides the scientific community with a larger arsenal of potential weapons that
may help bring the ongoing global pandemic to heel."


==========================================================================
The researchers are currently testing all 21 compounds in small animal
models and "mini lungs," or lung organoids, that mimic human tissue. If
these studies are favorable, the team will approach the U.S. Food and
Drug Administration (FDA) to discuss a clinical trial(s) evaluating the
drugs as treatments for COVID-19.

"Based on our current analysis, clofazimine, hanfangchin A, apilimod and
ONO 5334 represent the best near-term options for an effective COVID-19 treatment," says Chanda. "While some of these drugs are currently in
clinical trials for COVID-19, we believe it's important to pursue
additional drug candidates so we have multiple therapeutic options
if SARS-CoV-2 becomes drug resistant." Screening one of the world's
largest drug libraries The drugs were first identified by high-throughput screening of more than 12,000 drugs from the ReFRAME drug repurposing collection -- the most comprehensive drug repurposing collection of
compounds that have been approved by the FDA for other diseases or that
have been tested extensively for human safety.

Arnab Chatterjee, Ph.D., vice president of medicinal chemistry at
Calibr and co-author on the paper, says ReFRAME was established to
tackle areas of urgent unmet medical need, especially neglected tropical diseases. "We realized early in the COVID-19 pandemic that ReFRAME would
be an invaluable resource for screening for drugs to repurpose against
the novel coronavirus," says Chatterjee.



==========================================================================
The drug screen was completed as rapidly as possible due to Chanda's partnership with the scientist who discovered the first SARS virus,
Kwok-Yung Yuen, M.D., chair of Infectious Diseases at the University
of Hong Kong; and Shuofeng Yuan, Ph.D., assistant research professor in
the Department of Microbiology at the University of Hong Kong, who had
access to the SARS-CoV- 2 virus in February 2020.

About the ReFrame library ReFRAME was created by Calibr, the drug
discovery division of Scripps Research, under the leadership of
President Peter Shultz, Ph.D., with support from the Bill & Melinda Gates Foundation. It has been distributed broadly to nonprofit collaborators
and used to identify repurposing opportunities for a range of disease, including tuberculosis, a parasite called Cryptosporidium and fibrosis.

A global team The first authors of the study are Laura Riva, Ph.D.,
a postdoctoral research fellow in the Chanda lab at Sanford Burnham
Prebys; and Shuofeng Yuan at the University of Hong Kong, who contributed equally to the study. Additional study authors include Xin Yin, Laura Martin-Sancho, Naoko Matsunaga, Lars Pache, Paul De Jesus, Kristina
Herbert, Peter Teriete, Yuan Pu, Courtney Nguyen and Andrey Rubanov of
Sanford Burnham Prebys; Jasper Fuk-Woo Chan, Jianli Cao, Vincent Poon,
Ko-Yung Sit and Kwok-Yung Yuen of the University of Hong Kong; Sebastian Burgstaller-Muehlbacher, Andrew Su, Mitchell V. Hull, Tu-Trinh Nguyen,
Peter G.

Schultz and Arnab K. Chatterjee of Scripps Research; Max Chang
and Christopher Benner of UC San Diego School of Medicine; Luis Martinez-Sobrido, Wen-Chun Liu, Lisa Miorin, Kris M. White, Jeffrey
R. Johnson, Randy Albrecht, Angela Choi, Raveen Rathnasinghe, Michael Schotsaert, Marion Dejosez, Thomas P. Zwaka and Adolfo Garcia-Sastre of
the Icahn School of Medicine at Mount Sinai; Ren Sun of UCLA; Kuoyuan
Cheng of the National Cancer Institute and the University of Maryland;
Eytan Ruppin of the National Cancer Institute; Mackenzie E. Chapman,
Emma K. Lendy and Andrew D. Mesecar of Purdue University; and Richard
J. Glynne of Inception Therapeutics.

Research reported in this press release was supported by the National Institutes of Health (NIH) (U19AI118610, U19AI135972, HHSN272201700060C, GM132024, HHSN272201400008C, HR0011-19-2-0020, U19AI142733), the
Department of Defense (DoD) (W81XWH-20-1-0270), the Bill & Melinda
Gates Foundation, Dinah Ruch, Susan and James Blair, Richard Yu and
Carol Yu, the Shaw Foundation of Hong Kong, Michael Seak-Kan Tong, May
Tam Mak Mei Yin, the Health and Medical Research Fund (COVID190121),
the Food and Health Bureau, the Government of the Hong Kong Special Administrative Region; the National Program on Key Research Project
of China (2020YFA0707500, 2020YFA0707504), Research Grants Council (T11/707/15), the Huffington Foundation, the JPB Foundation, the Open Philanthropy Project (2020-215611 [5384]) and anonymous donors.


========================================================================== Story Source: Materials provided by Sanford_Burnham_Prebys_Medical_Discovery_Institute. Note: Content may
be edited for style and length.


========================================================================== Journal Reference:
1. Laura Riva, Shuofeng Yuan, Xin Yin, Laura Martin-Sancho, Naoko
Matsunaga,
Lars Pache, Sebastian Burgstaller-Muehlbacher, Paul D. De Jesus,
Peter Teriete, Mitchell V. Hull, Max W. Chang, Jasper Fuk-Woo
Chan, Jianli Cao, Vincent Kwok-Man Poon, Kristina M. Herbert,
Kuoyuan Cheng, Tu-Trinh H.

Nguyen, Andrey Rubanov, Yuan Pu, Courtney Nguyen, Angela Choi,
Raveen Rathnasinghe, Michael Schotsaert, Lisa Miorin, Marion
Dejosez, Thomas P.

Zwaka, Ko-Yung Sit, Luis Martinez-Sobrido, Wen-Chun Liu, Kris
M. White, Mackenzie E. Chapman, Emma K. Lendy, Richard J. Glynne,
Randy Albrecht, Eytan Ruppin, Andrew D. Mesecar, Jeffrey R. Johnson,
Christopher Benner, Ren Sun, Peter G. Schultz, Andrew I. Su,
Adolfo Garci'a-Sastre, Arnab K.

Chatterjee, Kwok-Yung Yuen, Sumit K. Chanda. Discovery of SARS-CoV-
2 antiviral drugs through large-scale compound repurposing. Nature,
2020; DOI: 10.1038/s41586-020-2577-1 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200724104221.htm

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