New paradigm of drug discovery with world's first atomic editing?

In pioneering drug development, the new technology that enables the easy and rapid editing of key atoms responsible for drug efficacy has been regarded as a fundamental and "dream" technology, revolutionizing the process of discovering potential drug candidates. KAIST researchers have become the first in the world to successfully develop single-atom editing technology that maximizes drug efficacy.

On October 8th, KAIST (represented by President Kwang-Hyung Lee) announced that Professor Yoonsu Park's research team from the Department of Chemistry successfully developed technology that enables the easy editing and correction of oxygen atoms in furan compounds into nitrogen atoms, directly converting them into pyrrole frameworks, which are widely used in pharmaceuticals.

This research was published in the scientific journal Science on October 3rd under the title "Photocatalytic Furan-to-Pyrrole Conversion."

Many drugs have complex chemical structures, but their efficacy is often determined by a single critical atom. Atoms like oxygen and nitrogen play a central role in enhancing the pharmacological effects of these drugs, particularly against viruses.

This phenomenon, where the introduction of specific atoms into a drug molecule dramatically affects its efficacy, is known as the "Single Atom Effect." In leading-edge drug development, discovering atoms that maximize drug efficacy is key.

However, evaluating the Single Atom Effect has traditionally required multi-step, costly synthesis processes, as it has been difficult to selectively edit single atoms within stable ring structures containing oxygen or nitrogen.

Professor Park's team overcame this challenge by introducing a photocatalyst that uses light energy. They developed a photocatalyst that acts as a "molecular scissor," freely cutting and attaching five-membered rings, enabling single-atom editing at room temperature and atmospheric pressure -- a world first.

The team discovered a new reaction mechanism in which the excited molecular scissor removes oxygen from furan via single-electron oxidation and then sequentially adds a nitrogen atom.

Donghyeon Kim and Jaehyun You, the study's first authors and candidates in KAIST's integrated master's and doctoral program in the Department of Chemistry, explained that this technique offers high versatility by utilizing light energy to replace harsh conditions. They further noted that the technology enables selective editing, even when applied to complex natural products or pharmaceuticals. Professor Yoonsu Park, who led the research, remarked, "This breakthrough, which allows for the selective editing of five-membered organic ring structures, will open new doors for building libraries of drug candidates, a key challenge in pharmaceuticals. I hope this foundational technology will be used to revolutionize the drug development process."

The significance of this research was highlighted in the Perspective section of Science, a feature where a peer scientist of prominence outside of the project group provides commentary on an impactful research.

This research was supported by the National Research Foundation of Korea's Creative Research Program, the Cross-Generation Collaborative Lab Project at KAIST, and the POSCO Science Fellowship of the POSCO TJ Park Foundation.

Journal Reference:

1. Donghyeon Kim, Jaehyun You, Da Hye Lee, Hojin Hong, Dongwook Kim, Yoonsu Park. Photocatalytic furan-to-pyrrole conversion. Science, 2024; 386 (6717): 99 DOI: 10.1126/science.adq6245 

Courtesy:

The Korea Advanced Institute of Science and Technology (KAIST). "New paradigm of drug discovery with world's first atomic editing?." ScienceDaily. ScienceDaily, 11 October 2024. <www.sciencedaily.com/releases/2024/10/241011141546.htm>.

 

 

 

 

Kerala is detecting ‘brain eating amoeba’ cases like never before – and saving its patients too

 

An alert medical fraternity and public, aggressive investigation, and a standard operating procedure – these are the major reasons why Kerala has been able to bring down mortality rate in the rare primary amoebic meningoencephalitis (PAM), commonly called the “brain eating amoeba”, from the 97 percent globally to 26 percent in Kerala.

Amoebic meningoencephalitis is caused by Naegleria fowleri, a free-living amoeba found in warm, fresh water and soil, and infects people when it enters the body through the nose.

According to the data submitted by Kerala health minister Veena George in the state Assembly early this week, of the 29 PAM cases that Kerala has reported so far in 2024, only five have died. State health department pegs the mortality rate for the disease at 26 percent – considerably lower than the 97 percent globally.

This is despite the jump in the number of cases in Kerala – according to state government data, cases have gone from just eight between 2016 and 2023 to 29 this year. Significantly, six districts had reported the PAM cases during the period, with Thiruvananthapuram having recorded the bulk of it at 15.

Of the 29 cases seen so far this year, 24 have survived. In contrast, according to the US Centres for Disease Control and Prevention, between 1962 and 2023, there were 164 reported cases of PAM in the United States, and only four survived.

The first case of PAM in India was reported in 1971, and the country has seen just around two dozen cases since then until last year. The first case in Kerala was reported in 2016.

All reported cases in India had led to the patient’s death – that is, until July this year, when 14-year-old Afanan Jasim from Thikkodi in Kerala’s Kozhikode district became the first Indian to survive the disease. He was only the 11th PAM survivor in the world.

The spike in cases this year is attributed to increased testing for acute encephalitis syndrome (AES) – a condition that can be caused by various diseases including amoebic meningoencephalitis – as well as other factors such as climate change and environmental pollution.

In July, Kerala issued a special treatment protocol and a standard operating procedure for the management of amoebic meningoencephalitis cases – the first state in India to do so.

According to Dr R Aravind, head of department of infectious diseases at the Government Medical College Thiruvananthapuram, the guidelines issued by the state health department on prevention, diagnosis and treatment of amoebic meningoencephalitis were a game changer for the state’s battle against the disease.

“The guidelines had stated a clear protocol to be followed, in which case one should suspect amoebic meningoencephalitis and what should be the medicine. Use of miltefosine was another major factor in the treatment, leading to reducing mortality. Until last year when we used a combination of four drugs (Amphotericin B, Rifampicin, Fluconazole and Azithromycin) and nobody survived. But the cocktail of these five drugs, including miltefosine, was another milestone in our fight against the fatal disease. As miltefosine was not easily available in India, the state health department took a very proactive stand and procured it from abroad.’

More cases are being detected because of aggressive search for amoebic meningoencephalitis cases.

Dr T S Anish, who is a member of the state medical board for PAM, said the increase in awareness of the disease among the doctors and the public helped detect more cases. According to him, the high instances of diagnosis of AES in the state was another major reason why doctors in Kerala were able to detect amoebic meningoencephalitis and Nipah cases more than anywhere else in the country.

“A few back-to-back deaths have also increased this awareness. Doctors have been sensitised. Now, if a patient is admitted with symptoms of encephalitis, they are ready to share the history of swimming in ponds or lakes, if any. This helps early diagnosis, which is vital for treatment of PAM. Thus, we have saved lives (in cases where PAM) would have gone undetected,” said Dr Anish, a professor of community medicine at the Government Medical College Manjeri, Malappuram.

The tropical climate of the state increases the chances of infection, he said.

“Due to global warming, the presence of naegleria fowleri has increased in ponds… We have other amoebae, too, which have become ubiquitous. But finding them is very tricky and there is a knowledge gap” he said.

Despite the fatality rate being pegged at 26 percent, sources in the health department believe the actual rate would be much lower.

According to the health department source, Kerala has reported two types of amoebae that cause brain infections. “We have cases reported from Kerala due to amoebas naegleria, which has a mortality rate of 97 percent, and acanthamoeba, which has mortality 60-90 percent. Hence, the state’s fatality rate was pegged at 26 percent,” the source said.

This finding of meningoencephalitis due to acanthamoeba, according to Dr Aravind, helped Kerala health department to go a step further in detecting the infection.

“When we were doing molecular diagnosis of meningoencephalitis, we learned that apart from naegleria fowleri, another genus acanthamoeba is also causing the infection. The notion that water exposure leads to amoebic meningoencephalitis is applicable only to cases caused by naegleria fowleri. Water exposure is not essentially applicable to meningoencephalitis caused by other amoeba including acanthamoeba, which has an incubation period from days to months,” he said.

Kerala had PAM cases without a history of water exposure, he said.

“The research papers published by School of Tropical Medicine, Kolkata, last year, had mentioned meningoencephalitis cases without water contact. Their experience also made us go for aggressive testing of meningoencephalitis cases without history of water contact. That helped us pick up more cases, particularly in Thiruvananthapuram,” he said.

Meanwhile, the state government has commissioned a study to analyse the organic and inorganic factors that contribute to increase in the density of amoeba in water bodies. The study will be conducted by Kerala University’s Department of Environmental Sciences and the State Pollution Control Board.

According to the University Prof Salom Gnana Thanka, who is part of the expert team, the density of amoeba will be high in contaminated water. “Besides, increase in temperature is also another contributing factor. We have literature from abroad in this regard but we have to study this situation in Indian conditions. We will be collecting samples of water mainly from areas where PAM cases were reported,” she said.

 https://indianexpress.com/article/india/kerala-is-detecting-brain-eating-amoeba-cases-like-never-before-and-saving-its-patients-too-9617472/

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