The American company Neuro-Horizon Pharma grants promising licenses

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image: The figure above shows two forms of mycobacterial colony formation. Mycobacterial F-ATP synthase (left) is the target of the new chemical compound, which is shown to be potent in killing the bacteria (right). (High resolution photo here).
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Credit: NTU Singapore

With multidrug-resistant tuberculosis (TB) causing epidemics in developing and developed countries, new treatments are urgently needed to control this infectious disease.

A series of chemical compounds that could be potential drug candidates in the fight against tuberculosis have been developed in Singapore.

The compounds are being developed by a joint team of Nanyang Technological University, Singapore (NTU Singapore) and the Investigational Drug Development Center (EDDC)a national drug discovery and development platform hosted by the Agency for Science, Technology and Research (A*STAR).

Neuro-Horizon Pharma LLC (PNS)a US-based drug development company, has been licensed to commercialize the compounds from NTU’s Innovation and Enterprise Company, NTUitivewho had filed patent applications for the compounds.

The World Health Organization[1] estimates that more than 1.5 million people die of tuberculosis worldwide, making it the second deadliest infectious disease after COVID-19.

Caused by bacteria Mycobacterium tuberculosistuberculosis is an infectious disease that has afflicted mankind for more than 70,000 years[2]with approximately 10 million new cases of tuberculosis per year.

Earlier in June, the Department of Health announced that 170 people had tested positive for tuberculosis in a large group[3] in Singapore. Tuberculosis is endemic in the developed city-state, and the prevalence of tuberculosis infection can reach 29% among people aged 70 to 79 years.

Founder and CEO of NHP Dr Vladimir Marshansky, said, “We are delighted to partner with NTU Singapore to develop compounds for the treatment of pulmonary tuberculosis, which remains a public health crisis today.

“Current regimens for treating TB are long and suffer from toxicity issues, while drug-resistant strains of the respiratory disease are increasingly prevalent, with only 1 in 3 people suffering from drug-resistant TB. having access to treatment,” Dr. Marshansky added.

This discovery was made possible thanks to a transdisciplinary platform called TOPNet (Targeting Oxidative Phosphorylation Network) supported by the National Research Foundation of Singapore [4](NRF Singapore).

TOPNET is led by NTU Professor Dr. Gerhard Grüber in collaboration with EDDC and Professor Thomas Dick from Hackensack Meridian Health Discovery and Innovation Center (CDI) in the USA.

Professor Grüber said developing innovative solutions to address some of humanity’s greatest challenges, such as ever-changing infectious diseases, is a key pillar of the NTU 2025 strategic plan.

“This partnership between NTU Singapore and NHP is a great example of how fundamental basic research at the University can yield great results years later, such as drug compounds that have a significant impact on public health. When we started our research, it was imperative that we understood all the key processes necessary for the survival of the tuberculosis bacteria. With this done, it was only then possible to identify key targets of adenosine triphosphate (ATP) processes that could prevent the multidrug-resistant tuberculosis bacterium from proliferating and replicating, thus opening up potential new treatment options,” said explained Professor Grüber.

These small molecule compounds have been shown to inhibit a key enzyme used by tuberculosis bacteria to produce ATP, an important molecule that is the primary source of energy for living cells.

At the molecular level, this ATP-producing enzyme resembles a nanometer-sized Wankel[5]-like a rotary engine that rotates to convert energy from one type to another type. If the enzyme ATP stops working, the process of producing ATP and the resulting energy supplied to the tuberculosis bacteria will be disrupted. It can be compared to how a car stops when its engine stops.

The path to the discovery and design of these small molecules was paved by previous NTU studies of the metabolism of drug-resistant tuberculosis, carried out by Prof Gruber, Associate Professor Roderick Wayland Bates of the Faculty of Physical and Mathematical Sciences and Associate Professor Kevin Petheprovost chair in infectious diseases at the Lee Kong Chian School of Medicine.

Researchers then combined their expertise in structural biology, mycobacterial physiology, bioenergetics, and drug discovery, with EDDC’s expertise and experience in drug design and medicinal chemistry, to successfully develop the lead series of inhibitors. small molecules.

Professor Damian O’Connell, CEO of EDDC, said, “As Singapore’s national drug discovery and development platform, EDDC works with key players in the local ecosystem to translate R&D into medicines that address unmet needs and improve the health of society. EDDC is proud to partner with NTU in the development of these small molecule inhibitors, and we look forward to NHP advancing these molecules as drug candidates for TB patients.

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[1] World Health Organization. (nd). Tuberculosis (TB). World Health Organization. Retrieved July 5, 2022, from https://www.who.int/news-room/fact-sheets/detail/tuberculosis

[2] Barberis I, Bragazzi NL, Galluzzo L, Martini M. The history of tuberculosis: from the first historical mentions to the isolation of Koch’s bacillus. J Prev Med Hyg. 2017 Mar;58(1):E9-E12. PMID: 28515626; PMCID: PMC5432783.

[3] Chew, E. (2022, June 25). Singapore expands TB controls after large cluster emerges. Bloomberg.com. Retrieved July 6, 2022, from https://www.bloomberg.com/news/articles/2022-06-25/singapore-widens-tuberculosis-checks-after-large-cluster-emerges

[4] NRF Research Grant Number: NRF-CRP18-2017-01

[5] https://en.wikipedia.org/wiki/Wankel_engine


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