{"id":3210,"date":"2023-01-22T17:09:59","date_gmt":"2023-01-22T23:09:59","guid":{"rendered":"https:\/\/kermitmurray.com\/msblog\/?page_id=3210"},"modified":"2023-01-22T17:09:59","modified_gmt":"2023-01-22T23:09:59","slug":"science-in-the-pipeline","status":"publish","type":"page","link":"https:\/\/kermitmurray.com\/msblog\/links\/journal-feeds\/science-journals\/science-journal\/science-in-the-pipeline\/","title":{"rendered":"Science in the Pipeline"},"content":{"rendered":"\n<div class=\"wp-block-caxton-grid relative\"><div class=\"absolute absolute--fill\"><div class=\"absolute absolute--fill cover bg-center\" style=\"background-color:;background-image:linear-gradient( );\"><\/div><div class=\"absolute absolute--fill\" style=\"background-color:;background-image:linear-gradient( );opacity:1;\"><\/div><\/div><div class=\"relative caxton-columns caxton-grid-block\" style=\"padding-top:0;padding-left:0;padding-bottom:0;padding-right:0;grid-template-columns:repeat(12, 1fr)\" data-tablet-css=\"padding-left:em;padding-right:em;\" data-mobile-css=\"padding-left:em;padding-right:em;\">\n<div class=\"wp-block-caxton-section relative\" style=\"grid-area:span 1\/span 8\"><div class=\"absolute absolute--fill\"><div class=\"absolute absolute--fill cover bg-center\" style=\"background-color:;background-image:linear-gradient( );\"><\/div><div class=\"absolute absolute--fill\" style=\"background-color:;background-image:linear-gradient( );opacity:1;\"><\/div><\/div><div class=\"relative caxton-section-block\" style=\"padding-top:5px;padding-left:5px;padding-bottom:5px;padding-right:5px\" data-mobile-css=\"padding-left:1em;padding-right:1em;\" data-tablet-css=\"padding-left:1em;padding-right:1em;\">\n<p><strong><a href=\"https:\/\/www.science.org\/content\/page\/email-alerts-and-rss-feeds\" target=\"_blank\" rel=\"noreferrer noopener\">Journal Home<\/a><\/strong><\/p>\n<\/div><\/div>\n\n\n\n<div class=\"wp-block-caxton-section relative\" style=\"grid-area:span 1\/span 4\"><div class=\"absolute absolute--fill\"><div class=\"absolute absolute--fill cover bg-center\" style=\"background-color:;background-image:linear-gradient( );\"><\/div><div class=\"absolute absolute--fill\" style=\"background-color:;background-image:linear-gradient( );opacity:1;\"><\/div><\/div><div class=\"relative caxton-section-block\" style=\"padding-top:5px;padding-left:5px;padding-bottom:5px;padding-right:5px\" data-mobile-css=\"padding-left:1em;padding-right:1em;\" data-tablet-css=\"padding-left:1em;padding-right:1em;\">\n<p><strong><a href=\"https:\/\/www.science.org\/blogs\/pipeline\/feed\" target=\"_blank\" rel=\"noreferrer noopener\">RSS<\/a><\/strong><\/p>\n<\/div><\/div>\n<\/div><\/div>\n\n\n<ul class=\"has-dates has-authors has-excerpts wp-block-rss\"><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/progress-against-pancreatic-cancer-part-one'>Progress Against Pancreatic Cancer, Part One<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">We have some really interesting progress in pancreatic cancer to talk about, both on the small-molecule and the mRNA vaccine fronts. Let\u2019s do the small-molecule ones first, because those were honestly more unexpected. So to lead off, Revolution Medicines announced at the AACR meeting in San Diego that their drug daraxonrasib showed strong efficacy in patients with metastatic pancreatic ductal adenocarcinoma (PDAC). That is a very, very difficult to treat population &#8211; these people typically have only a few months [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/lyme-vaccines-past-and-possibly-future'>Lyme Vaccines, Past and Possibly Future<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Living in New England, we tend to get out into the yards, parks, and gardens this time of year because we\u2019ve pretty much had it with winter. Of course, winter hasn\u2019t always had it with us &#8211; we\u2019ve had frost here the last couple of mornings, so it\u2019s not exactly time to put the tomatos and cucumbers out there yet. But whenever the weather does start to warm up, so (unfortunately) does the threat of tick-borne diseases like Lyme. That [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/bizarre-viruses-indeed'>Bizarre Viruses Indeed<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Translation of mRNA into proteins is a nonstop, nonnegotiable process that is essential to the life of a cell, and it has acquired a *lot* of evolutionary tuning over the last few billion years. In critters like us with nuclei and other such organelles (the big happy club of eukaryotes, to which so many of my readers belong as G. K. Chesterton used to say), there\u2019s a very important protein complex called elF4F. That\u2019s short for \u201ceukaryotic initiation factor 4F&quot;, [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/anti-amyloid-antibodies-alzheimer-you-already-know'>Anti-Amyloid Antibodies for Alzheimer: You Already Know<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">This is not going to come as a surprise to readers of this site, because even if you don\u2019t agree with this contention you have certainly at least been exposed to it: the Cochrane Review folks have examined the clinical evidence for anti-amyloid antibodies as therapies for Alzheimer\u2019s and found, well. . .you know what they found: The effect of amyloid\u2010beta\u2010targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/antimalarial-drugs-stepping-each-other-s-toes'>Antimalarial Drugs Stepping On Each Other&#039;s Toes<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Artemisinin-based therapies are the absolute mainstay of malaria treatment the world over, so this new paper deserves attention. The drug is often given in combination with the older aminoquinoline agents like choloroquine, piperaquine, and amodiaquine, but the authors here make a strong case that this is actually counterproductive. As the paper notes, heme is central to the mechanism of action for both kinds of drugs. The aminoquinolines bind to it and affect heme homeostasis, and may well product toxic adducts [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/answers-and-reasons-and-knowing-and-thinking'>Answers and Reasons and Knowing and Thinking<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">I spent a day at Williams College last week, which I enjoyed very much, and I found a part of my lecture there overlapping with a big topic in undergraduate education. I have a section in several of my talks where I speak about AlphaFold-type machine learning and its implications for drug discovery, and that seemed to fit rather closely into concerns that many professors are having about the effect of AI systems on coursework and learning. I\u2019m sure that [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/predicting-antibody-binding-no-champagne-just-yet'>Predicting Antibody Binding: No Champagne Just Yet<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">I often get asked what areas of drug discovery look most likely to bear AI-driven advances into the clinic, and my usual answer is \u201ctherapeutic antibodies\u201d. Thats because it\u2019s a protein-centric problem in the actual modeling, and we know quite a bit already about antibody structures (at least as compared to the much large wild-type protein structural landscape). And that\u2019s because antibodies themselves are a (relatively!) constrained space within that larger one, although don\u2019t let anyone tell you that it\u2019s [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/consider-selfish-ribosome'>Consider the Selfish Ribosome<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">If you look at cells dispassionately, one of the things that strikes is that man, do we ever have a lot of ribosomes. These are of course the protein-synthesis machines that are kept humming nonstop as RNA sequences are translated into protein sequences, and ribosomes themselves are structurally a mixture of proteins and some unusual RNA molecules all their own. The peptidyltransferase center (PTC) where the actual synthesis of new peptide bonds takes place is itself a flat-out ribozyme, an [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/new-bond-formations-just-keep-coming'>New Bond Formations Just Keep On Coming<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Longtime readers will recall the fuss I made about the \u201csynthesis machine\u201d work from the Burke group at Illinois. That involved iterative coupling of boronic esters with MIDA boronates, which were then deprotected to plain boronic esters, which could then be coupled with a further MIDA boronate, and you get the idea. It\u2019s a scheme for directed carbon-carbon bond formation, and when you get down to it, a lot of organic synthesis is in fact a scheme for directed carbon-carbon [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/ah-peptides-where-begin'>Ah, Peptides. Where to Begin?<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">So let\u2019s finally talk about peptides. And I don\u2019t mean peptides as chemists and biologists understand them (short chains of amino acids) I mean \u201cPeptides!\u201d, the hot new wonder drugs that you can order by mail. Oh man. The first barrier to writing about this situation, for someone like me, is that difference in terms. For a chemist, \u201cpeptide\u201d has a pretty clear definition: any relatively short chain of amino acids, and when they get longer we go ahead and [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/new-opioid-agonist'>A New Opioid Agonist?<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Here\u2019s an interesting surprise: an opiod agonist with what seems to be fewer side effects. That\u2019s been a tricky thing to manage &#8211; all the morphine-type compounds have the well-known liabilities (addictive potential, respiratory depression, gut motility and more), and the synthetic ligands like fentanyl certainly don\u2019t avoid these either. In recent years there\u2019s been a revival of interest in an older class of molecules called nitazenes, but unfortunately a big part of that interest has come from drug cartels: [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/say-chameleonicity-three-times-fast-or-read-post'>Say &quot;Chameleonicity&quot; Three Times Fast. Or Read This Post.<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">By this point a lot of companies have made a lot of PROTAC bifunctionals. Those, as my readers in the business well know, are large species that have two \u201cbusiness ends\u201d tied together by some sort of linking group. One end binds to a protein of interest (POI) and the other to a protein that is involved in the protein degradation machinery (typically an E3 ligase enzyme). Having these in the same molecule lets you bind to your target and [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/right-through-skull'>Right Through the Skull<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">In today\u2019s \u201cWell, I\u2019ll be darned\u201d category is this paper, which described a way to get drug delivery into the brain that I never would have imagined. The authors are using a \u201ccalvarial\u201d mechanism, and I\u2019m certainly in a forgiving mood if you\u2019ve never heard that word before, because I certainly hadn\u2019t. The calvaria, as it turns out, is the top of the skull, and the skull bones have a lot of anatomical detail in them. The inner and outer [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/revving-lnp-delivery'>Revving Up LNP Delivery<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Now here\u2019s something that I wouldn\u2019t have guessed. As the world knows, lipid nanoparticles have been the key to getting mRNA vaccines to work, and they are useful for all other attempts to deliver RNA cargoes into cells and probably much besides. A huge amount of effort, time, and money has been put into trying to optimize them for these purposes &#8211; all sorts of different lipids and lipid mixes, close attention to size, morphology, and cargo loading, you name [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/latest-car-t-work'>The Latest CAR-T Work<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">The development of chimeric antigen receptor T-cell (CAR-T) therapy continues, and some really interesting new directions are being explored. As it stands, this treatment can be extraordinarily effective in some patients, and these are generally people who have been through every other option for their cancer therapy. But there are some real limitations, even for treating patients with the leukemia\/myeloma type cancers that (so far) this mode is best suited for. An obvious one is the sheer amount of time [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/fentanyl-s-membrane-behavior'>Fentanyl&#039;s Membrane Behavior<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Here\u2019s a look at one of the most famous opioid agonists in the world, fentanyl. You might think that by this point we would have a pretty thorough understanding of the drug\u2019s behavior and the factors that lead to its (notorious) potency, but such GPCR ligands it seems that there\u2019s always more to discover. The authors here are working off recent results from patch-clamp receptor assays in whole cells that suggested that fentanyl (but not the classic opioid ligand morphine) [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/set-phasers-kill-no-not-those-phasers'>Set Phasers to &quot;Kill&quot;. No, Not Those Phasers.<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Time to think like a biochemist! And that means paying close attention to energy transactions in a cell, because the science of thermodynamics makes it very, very clear there there is always a bill that has to be paid. Most of the time, the currency involved is of course ATP, since breaking that down to ADP gives you an immediate payout. ATP hydrolysis and the other sources of chemical energy (like acetyl-CoA) function as \u201cbattery packs\u201d for all sorts of [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/ai-predicting-compound-affinity-we-aren-t-there-yet'>AI-Predicting Compound Affinity. We Aren&#039;t There Yet.<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Here\u2019s a paper evaluating a popular AI\/ML model for cofolding ligands and proteins, Boltz-2. This is of course a problem of extreme interest to the drug discovery community, as well as to all sorts of people working on cell biology, structural biology, and related fields. It\u2019s been one of the goals for decades to start from scratch with a protein sequence and a small molecule and be able to say \u201cDoes this molecule bind to this protein? How well?\u201d And [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/gut-bacteria-brain'>From Gut Bacteria Up to the Brain<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">Here\u2019s the other cognition\/aging\/Alzheimer\u2019s paper that caught my eye. In a similar way to the work I highlighted yesterday on proteins released by the liver affecting the blood-brain barrier and overall brain function, this one is finding another external signal, from from an unexpected direction. The authors studied the intestinal microbiomes of mice as they aged, and found that species that produce medium-chain fatty acids become more and more prevalent. Then a complex series of events start taking place: these [&hellip;]<\/div><\/li><li class='wp-block-rss__item'><div class='wp-block-rss__item-title'><a href='https:\/\/www.science.org\/content\/blog-post\/beneficial-effects-liver-brain'>Beneficial Effects From the Liver to the Brain<\/a><\/div><div class=\"wp-block-rss__item-excerpt\">I\u2019d like to highlight a couple of interesting papers with a bearing on Alzheimer\u2019s and aging in general &#8211; well, I hope that they will turn out to have one, because right up front I have to note that they\u2019re both in rodent models. But the unusual mechanisms in both cases are the sort of thing that could translate to humans, and could also be fairly readily checked. We\u2019ll do one today and another tomorrow. This paper is building on [&hellip;]<\/div><\/li><\/ul>\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity is-style-wide\"\/>\n\n\n\n<h4 class=\"wp-block-heading\">Related Journals<\/h4>\n\n\n<ul class=\"su-siblings\"><li class=\"page_item page-item-3212\"><a href=\"https:\/\/kermitmurray.com\/msblog\/links\/journal-feeds\/science-journals\/science-journal\/science-first-release\/\">Science First Release<\/a><\/li>\n<li class=\"page_item page-item-3208\"><a href=\"https:\/\/kermitmurray.com\/msblog\/links\/journal-feeds\/science-journals\/science-journal\/science-podcast\/\">Science Podcast<\/a><\/li>\n<\/ul>\n","protected":false},"excerpt":{"rendered":"<p>Related Journals<\/p>\n","protected":false},"author":1,"featured_media":3202,"parent":3204,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":{"footnotes":"","_links_to":"","_links_to_target":""},"class_list":["post-3210","page","type-page","status-publish","has-post-thumbnail","hentry","entry"],"_links":{"self":[{"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/pages\/3210","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/comments?post=3210"}],"version-history":[{"count":1,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/pages\/3210\/revisions"}],"predecessor-version":[{"id":3211,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/pages\/3210\/revisions\/3211"}],"up":[{"embeddable":true,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/pages\/3204"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/media\/3202"}],"wp:attachment":[{"href":"https:\/\/kermitmurray.com\/msblog\/wp-json\/wp\/v2\/media?parent=3210"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}