May 7, 2024

We’ve all heard of The Magic School Bus – a fictional children’s program exploring the inner workings of science through a series of field trips. The Magic School Bus could go anywhere and teach anything, be it the human body, the rings of planet Saturn, or the depths of the ocean. 


Now imagine this: a magical library full of natural compounds made by microorganisms with the power to act against infectious diseases, cancer and neurological disorders – helping drive research towards treatments and cures. Except it’s not magic, it’s a real resource within the walls of the Life Sciences Institute (LSI), a world-class laboratory facility at the University of Michigan. David Sherman, PhD, a Professor of Medicinal Chemistry at the University of Michigan College of Pharmacy has researched natural compounds for 30 years and along with other Pharmacy faculty like Roland Kersten, Marcy Balunas and Ashootosh Tripathi has been collecting chemical compounds in nature and adding to the Natural Products Discovery Core at U-M. 


Dr. Sherman’s work knows no bounds and no borders. Over his career, he has traveled to places like Papua New Guinea, Costa Rica, and Peru, receiving permission in compliance with local, federal, and international laws to collect natural compound source materials from the ocean, including sediment from coral reef systems. Back home in the lab, Sherman and his team work to culture new bacterial species from marine sediments and soils. Once grown, researchers can begin to investigate them for medicinal properties. 


This Natural Products Discovery Core library offers biomedical researchers access to more than 50,000 extracts from 10,000 pure-culture microbes. Scientists in the pharmaceutical industry and across the University of Michigan and other institutions who have a biological target involved in a disease they are studying can efficiently test that target against this huge library of natural compounds and hone in on those that spark a beneficial response. 


Microbes found in nature are known to mount a sophisticated response to environmental stress or predators, developing diverse small molecule metabolites to defend themselves from threats. The library of natural samples helps scientists exploit these evolved defenses and redirect them against human diseases.


Although this library is first in its class, utilizing natural products as drug leads isn’t new practice. In fact, according to the University of Michigan Life Sciences Institute, roughly half of drugs used in clinical practice today originated from molecules that evolved inside microorganisms or plants. In fact, a survey of 246 antitumor drugs approved by the FDA between the late 1940’s and 2014 shows that more than 65 percent of them are either natural products or are modified forms of natural product scaffolds. 


The Natural Products Library’s Impact on Drug Discoveries 

Over the past decade, the University of Michigan has become a leader in natural product sciences. The library has been essential for a breadth of research projects including discovering novel therapeutics for treating fibrotic disease and characterizing metabolic signatures in patients with lung cancer. Most recently, the natural products library was utilized by Kathleen Collins, MD, PhD, in her collaborative research with Dr. Sherman to find a cure for the human immunodeficiency virus, or HIV. 


HIV, the virus that causes acquired immunodeficiency syndrome, attacks and cripples, white blood cells, leaving the body vulnerable to infections, illnesses and certain cancers. Because the virus stealthily hides itself in the DNA of infected cells, we can manage the infection but we can’t target and inactivate it to cure the disease. 


Dr. Collins' research led to the discovery of a protein unique to HIV called Nef that helps the virus hide from our immune system. She has spent years screening thousands of synthetic compounds to reverse the effects of Nef without success. A colleague suggested she reach out to Dr. Sherman’s lab to screen molecules from the natural products library. Intrigued, she did. The team at the Natural Products Discovery Core quickly found a highly potent compound that inhibited Nef to re-establish an effective immune response against HIV, Sherman said. 


The findings of that study were recently published in the Journal of Medicinal Chemistry. The Sherman/Collins team discovered that a modified form of the natural substance called Concanamycin A – found in a marine sample Sherman collected many years ago near Papua New Guinea – can disable Nef based on a new mechanism that can help the immune system recognize and fight off HIV infected cells. 


“There is much more information to be gathered about how this drug may react inside a living body, but this is very promising research toward our quest to develop a drug with the ability to eradicate HIV.” says Dr. Sherman 


Library of Endless Discoveries

The Natural Products Discovery Core library is a unique resource for researchers to screen novel biological targets for drug discovery using state-of-the-art equipment. 


David Sherman, PhD, is a shining example of the commitment to exploring new frontiers in drug discovery within the College of Pharmacy, and the University of Michigan as a whole.





Structure–Activity Relationships of Natural and Semisynthetic Plecomacrolides Suggest Distinct Pathways for HIV-1 Immune Evasion and Vacuolar ATPase-Dependent Lysosomal Acidification
Morgan McCauley, Matthew Huston, Alanna R. Condren, Filipa Pereira, Joel Cline, Marianne Yaple-Maresh, Mark M. Painter, Gretchen E. Zimmerman, Andrew W. Robertson, Nolan Carney, Christopher Goodall, Valeri Terry, Rolf Müller, David H. Sherman, and Kathleen L. Collins
Journal of Medicinal Chemistry Article 2024. 67(6):4483-4495
DOI: 10.1021/acs.jmedchem.3c01574