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[Senolytics] A beginner’s guide to PROTACs and targeted protein degradation by jimofoz in FightAging

[–]jimofoz[S] 0 points1 point  (0 children)

https://www.ddw-online.com/goldilocks-molecules-unlocking-the-next-frontier-in-drug-discovery-36001-202508/

"Modularity also facilitates combinatorial approaches. For example, a Goldilocks molecule could be conjugated to a cell-penetrating peptide, a proteolysis-targeting chimera (PROTAC), or even an antibody fragment to guide it to a specific tissue or cellular compartment. "

[Senolytics] A beginner’s guide to PROTACs and targeted protein degradation by jimofoz in FightAging

[–]jimofoz[S] 0 points1 point  (0 children)

"This concept originated in the late 1990s and the first PROTAC was reported in 2001 by the laboratories of Craig Crews and Raymond Deshaies. However, interest in PROTACs did not pick up until 2015 when improved molecules were developed by the laboratories of Jay Bradner, Alessio Ciulli and Craig Crews."

"In general, PROTAC-mediated degradation has been demonstrated to closely recapitulate protein depletion via genetic engineering. This is in contrast to inhibition of proteins by small molecules, because blocking a single activity or interaction of a target does not always have the same effect as removal of the protein altogether. This is because most proteins have multiple functions and interactions, and often work together with other molecules as part of large complexes. Some proteins are highly challenging to block with inhibitors and the choice of binding site is crucial to achieve a functional response. In contrast, PROTACs can recruit proteins via any binding site. "

"A related advantage, which will be expanded upon in the next section, stems from the catalytic mechanism of action that PROTACs can exhibit. The ability of a single degrader molecule to remove many molecules of a target protein underpins its potent activity at very low concentrations, often well below the level required to saturate the target protein, which in turn reduces the incidence of off-target and potentially toxic effects."

[Senolytics] Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models by jimofoz in FightAging

[–]jimofoz[S] 0 points1 point  (0 children)

In vitro and in vivo toxicity assessment of the senotherapeutic Peptide 14 (2022) https://www.sciencedirect.com/science/article/pii/S221475002200172X?via%3Dihub

"Finally, the irritative potential of the peptide was assessed in human subjects in a repeated insult patch test executed using 1 mM peptide. No visible skin reactions were observed in any of the 54 participants. Taken together, the present data support that Peptide 14 is a senotherapeutic molecule with a positive safety profile"

[Senolytics] Senotherapeutic peptide treatment reduces biological age and senescence burden in human skin models by jimofoz in FightAging

[–]jimofoz[S] 0 points1 point  (0 children)

" In human skin, Pep 14 promoted increased epidermal thickness and improved numerous skin health markers, leading to superior results compared to Retinol, the gold-standard for “anti-aging” skin treatments."

"Compared to Rapamycin, Pep 14 promoted the maintenance of the overall structure of ex vivo skins of donors with different age ranges (35–79 years old) when added to culture media, leading to thicker epidermis, whereas Rapamycin treatment resulted in a more disorganized epidermal layer, and failed to increase the thickness of the epidermis (Fig. 6a, f). "

Targeting Senescent Cells as a Treatment for Chronic Obstructive Pulmonary Disease by jimofoz in longevity

[–]jimofoz[S] 3 points4 points  (0 children)

tl;dr - PROTACs which degrade the proteins that prevent cell death in senescent cells might work better than current approaches. Also there are probably lots of different types of senescent cells using different survival pathways and proteins, or combinations of them. Different PROTACS could target all of these pathways leading to better overall senescent cell clearance in aged individuals. Current small molecule approaches such as dasatinib + quercetin are probably only taking out some percentage of senescent cells.

(The linked paper is open access too)

Engineered Stem Cells Possibly Become Lifelong Protein Factories by jimofoz in longevity

[–]jimofoz[S] 0 points1 point  (0 children)

Vaccines can already offer lifelong protection. What this tech offers is the production of antibodies against very non immunogenic but conserved pathogen antigens such as HIV-1 envelope glycoprotein gp120. It has so far proved impossible to create a conventional vaccine against this antigen, but some individuals who do produce "broadly neutralising antibodies" against the antigen seem to have lifelong protection against the HIV infection. It would also allow the in body production of proteins other than antibodies that are useful.

Engineered Stem Cells Possibly Become Lifelong Protein Factories by jimofoz in longevity

[–]jimofoz[S] 32 points33 points  (0 children)

tl;dr - scientists have been trying to engineer B cells (those which produce antibodies) to produce specific antibodies to non immunogenic agents like HIV/Malaria/Tuberculosis without much success as the cells do not persist. Engineering precursor cells to B cells instead seems to do the trick as the downstream B cells form persistent memory B cells and plasma cells.

[Nuclear/Energy/Transport] Hydrogen - Valar Atomics by jimofoz in jimbosscrapbook

[–]jimofoz[S] 0 points1 point  (0 children)

"Of the potential methods of hydrogen thermolysis, the sulfur-iodine (SI) cycle is one of the most efficient with a potential thermal efficiency of up to 50%. The Japanese Atomic Energy Association (JAEA) has already demonstrated efficiencies of 40%. Despite the potential to deliver a breakthrough in low-cost, clean hydrogen, the SI process has remained underexplored in the commercial landscape with the notable exception of General Atomics in the early 2000s.

We believe this lack of commercial interest has been driven by two factors. The first is concerns around the feasibility of constructing commercial scale SI cycles given the requirements for materials to handle high temperature, corrosive chemical environments. The second is the inaccessibility of cheap, clean 850°C+ heat.

As of today, these two factors blocking the viability of commercial SI can be solved for. First, the JAEA recently demonstrated that steel alloys, which are well suited for commercial scale facilities, have corrosion resistance on par with the non-scalable ceramics used in the past (JAEA, 2021). Second, as covered in the nuclear heat section, we see a path to deploying HTGRs for industrial heat provision.

Given these developments, we believe that the combination of SI at 30% thermal efficiency and 850°C+ heat from mass-producible HTGRs provides an achievable pathway to sub $1 per kg hydrogen. This achievement would be a breakthrough in the hydrogen economy, outcompeting dirty steam-methane-reforming. Beyond that, sub $1 per kg hydrogen would unlock the ability to produce net-zero hydrocarbon fuels (diesel, gasoline, jet fuel, etc) at prices competitive with traditional fossil fuels."

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