Integrated Biosciences, a biotechnology company combining synthetic biology and machine learning to target aging, in collaboration with researchers at the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard, today announced results demonstrating the power of artificial intelligence (AI) to discover novel senolytic compounds, a class of small molecules under intense study for their ability to suppress age-related processes such as fibrosis, inflammation and cancer. A new publication authored by company founders in Nature Aging, “Discovering small-molecule senolytics with deep neural networks,” describes the AI-guided screening of more than 800,000 compounds to reveal three drug candidates with comparable efficacy and superior medicinal chemistry properties than those of senolytics currently under investigation.

Senolytics are an emerging class of investigational drug compounds that selectively kill aging-associated senescent cells (left, with red stain) without affecting other cells (right). Using artificial intelligence, researchers from Integrated Biosciences have, for the first time, identified three senolytics with comparable efficacy and superior drug-like properties relative to leading investigational compounds. 

“This research result is a significant milestone for both longevity research and the application of artificial intelligence to drug discovery,” said Felix Wong, Ph.D., co-founder of Integrated Biosciences and first author of the publication. “These data demonstrate that we can explore chemical space in silico and emerge with multiple candidate anti-aging compounds that are more likely to succeed in the clinic, compared to even the most promising examples of their kind being studied today.”

Senolytics are compounds that selectively induce apoptosis, or programmed cell death, in senescent cells that are no longer dividing. A hallmark of aging, senescent cells have been implicated in a broad spectrum of age-related diseases and conditions including cancer, diabetes, cardiovascular disease, and Alzheimer’s disease. Despite promising clinical results, most senolytic compounds identified to date have been hampered by poor bioavailability and adverse side effects. Integrated Biosciences was founded in 2022 to overcome these obstacles, target other neglected hallmarks of aging, and advance anti-aging drug development more generally using artificial intelligence, synthetic biology and other next-generation tools.

“One of the most promising routes to treat age-related diseases is to identify therapeutic interventions that selectively remove these cells from the body similarly to how antibiotics kill bacteria without harming host cells. The compounds we discovered display high selectivity, as well as the favorable medicinal chemistry properties needed to yield a successful drug,” said Satotaka Omori, Ph.D., Head of Aging Biology at Integrated Biosciences and joint first author of the publication. “We believe that the compounds discovered using our platform will have improved prospects in clinical trials and will eventually help restore health to aging individuals.”

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When therapeutics battle HIV, they tend to miss pockets of resistance where HIV can hunker down until it stages a comeback. HIV, then, cannot be defeated until its remnants are roused to action, and its hiding places exposed and eliminated. This two-step strategy is called “shock and kill.” It sounds promising, but shock and kill hasn’t quite worked yet. It still needs the right shock.

Encouragingly, a better shock has been proposed by scientists at Sanford Burnham Prebys Medical Discovery Institute. These scientists, led by Sumit Chanda, PhD, director and professor and Nicholas Cosford, PhD, deputy director of the NCI-designated Cancer Center at Sanford Burnham Prebys and co-senior author of the study, have identified a drug that reawakens the virus without activating the immune system. That is, the drug makes it possible to save the immune system without having to destroy it.

“What scientists have found with other ‘shock’ approaches is that they can be too hot and overactivate the immune system, or too cold and don’t wake up the virus,” said Chanda. “Our research identifies a drug that works in the ‘Goldilocks’ zone.”

The drug is a Smac mimetic called Ciapavir (SBI-0953294). Smac mimetics are a class of small-molecule peptidomimetics derived from a conserved binding motif of Smac (second mitochondria-derived activator of caspases), an endogenous protein inhibitor of apoptosis. Originally developed as cancer drugs, Smac mimetics are being evaluated for other purposes, such as fighting HIV.

Repurposed Smac mimetics have had modest success in reversing HIV latency. In hopes of building on this success, Chanda, Cosford, and colleagues decided to experiment with a Smac mimetic optimized to reverse HIV latency. The results of this work appeared June 23 in Cell Reports Medicine, in an article titled, “Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo.” According to this article, Ciapavir is more efficacious as a latency-reversing agent than other drugs of its class.

“Ciapavir induced activation of HIV-1 reservoirs in vivo in a bone marrow, liver, thymus (BLT) humanized mouse model without mediating systemic T cell activation,” the article’s authors wrote. “This study provides proof of concept for the in vivo efficacy and safety of Ciapavir and indicates that Smac mimetics can constitute a critical component of a safe and efficacious treatment strategy to eliminate the latent HIV-1 reservoir.”

Source: https://www.genengnews.com/

All cells in the human body have a shelf-life, but those of the cancerous variety use some cunning trickery to outlive their expiry dates and continue spreading throughout the body. Scientists at the University of Tokyo have developed a synthetic version of a fungal compound that could help swing things back in our favor, by reactivating a missing gene that would normally drive these sinister cells to self-destruction.

As our cells fulfill their roles and edge towards the end of their lives, they undergo a form of programmed death called apoptosis, clearing the way for fresher and healthier cells. But with the help of genetic mutations, cancer cells are able to avoid this fate and go on multiplying to form tumors.

Targeting this mechanism and initiating apoptosis in cancer cells has been a major focus for researchers in the field, with compounds in olive oil and others that flush them with salt a couple of techniques that have shown promise in recent times. And in a naturally occurring compound found in the fungus species Ascochyta, scientists uncovered another exciting possibility.

Previous experiments had shown this compound, called FE399, could trigger apoptosis in cancer cells in vitro, by reinstating the self-destruct gene that drives the programmed death process. The compound had shown particular promise against colorectal cancer, but the complex nature of the compound meant that reproducing it in meaningful quantities was a tall order. Extracting natural versions of FE399 from the fungus was not a viable option, setting up a significant roadblock for use of this promising anti-cancer compound. But the University of Tokyo team was determined to find a way forward, and set out to develop a complete, synthetic version of the compound to pave the way for mass production.

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“We wanted to create a lead compound that could treat colon cancer, and we aimed to do this through the total synthesis of FE399,” says Professor Isamu Shiina, study author.

The team started by identifying the complex structure of the compound. A long process of trial and error followed until, in what the researchers describe as a major breakthrough, they produced a trio of spots on a plate bearing exactly the same chemical signature as FE399.

“We hope that this newly produced compound can provide an unprecedented treatment option for patients with colorectal cancer, and thus improve the overall outcomes of the disease and ultimately improve their quality of life,” says Professor Shiina.

The research was published in the journal European Journal of Organic Chemistry.

Source: https://newatlas.com/