 Thank you for introducing our work to the public. My name is Sridhar Mani. I'm a researcher at the Albert Einstein College of Medicine in Bronx, New York, and I have a laboratory that works and has expertise on the study of orphan nuclear receptors. We have an evolving story that I think might be of interest to the general scientific and non-scientific audience, and that stems from our work in 2000, which was published in 2014. So we work with a receptor, a specific orphan nuclear receptor called the Pregname X receptor. It's a X stands for xenobiotic. So it's a nuclear receptor, which is a protein that resides in the nucleus of a cell. And when bound to a xenobiotic, meaning a compound that is foreign to the body, that it activates and induces a program, a gene transcriptional program, a variety of genes that traditionally was ascribed to drug metabolism or xenobiotic metabolism. That was a paradigm. The gene was cloned by several groups and is still the paradigm. However, there are many other functions of the receptor that we have uncovered over the years and an enigmatic function of the receptors. What is it doing in both the liver where it's expressed and in the intestines where it's expressed when there is no xenobiotic? Is the receptor important at all? What's its physiologic function, so to speak? And a lot of work that led to a paper culminating in 2014 in immunity, we were able to show that with the loss of the receptor, and we obviously used mouse systems to show this, that in the intestines, there is an increase in the permeability, as well as gradual inflammation that takes place. So the receptor, as others have already shown, that the receptor had potential to abrogate or inhibit inflammation, that it makes sense that its loss in steady state in homeostasis in the physiologic state would also portend higher degrees of inflammation with age. So we got interested as to what and how this may happen and to break a long story. We were able to hone down on metabolites that were generated. These are breakdown products of agents that we consume in our diet, for example. So these were bacterial metabolites of those agents, a breakdown product of it, whether those products were actually serving as ligands that bound to our receptor. This would mean it would be an endobiotic, meaning it's not foreign to us. It's not a xenobiotic, but it's within us that we create these little ligands. And it made sense because bacteria that houses basically every orifice of our body, especially in the intestines, there are 100-fold more genes in bacteria. There's a lot more metabolic repertoire for bacteria to produce ligands which are free-floating in the intestine, and they have some place to go, either be absorbed or be secreted out of the body. So we felt that these metabolites that are formed in the intestines might be very good ligands if we could parse them out and show that indeed there are such ligands that exist for PXR in the gut or the intestine. And indeed we were able to show that certain bacteria that break down the metabolism of L-tryptophan to endopropionic acid is a metabolite of the breakdown of L-tryptophan in the gut by microbes. And that endopropionic acid indeed is a receptor or is a ligand for the receptor PXR. And we were able to show that indeed endopropionic acid has weak activity against other receptors, including the aryl hydrocarbon receptor. So armed with this and the fact that the human receptor of the Pregnane X receptor, the human PXR as opposed to the mouse PXR was a little more complicated. You needed a combinatorial addition of ligands. So for example it had to bind to indole as well as endopropionic acid and there were other combinations which made more sense because in our body we are producing all these ligands simultaneously. So there's no reason to invoke only one ligand as binding to a receptor. There has to be its combinatorially presented to the cell which has the receptor of interest in our case PXR and in humans it would try to map the landscape really of what is there and if the right combination of ligands were present at the right concentrations it would then engage those ligands simultaneously. And we knew this also because the human Pregnane X receptor has a very large ligand binding pocket, much larger than most receptors, it's not all receptors cloned to date. So it has that promiscuity which acts in it probably in its favor in the intestine where it is sort of sensing what's going on all the time, what's being produced combinatorially and what it can bind combinatorially and that also gives it context specificity because at a particular point of time when these combinations are in the right mode mix it'll activate, when they're not it'll not active. So armed with this data we were able to model based on a variety of crystal structures that were already published by several other groups including Matt Redenbos group at the University of North Carolina who's really spearheaded the crystallization of this receptor initially and we were able to show that indeed that you could model these small molecule metabolites combinatorially on within the PXR ligand binding domain. And in fact that led to looking at the pharmacophore, the space by which these ligands come together within the ligand binding cavity as a means to see whether we could convert all this information pharmacologic information to a single molecule that would be synthesis of a single indolic derivative that would sort of have the same binding mode as the combination of these little indoles metabolites that are being formed in the intestine. So based on this and collaborations with other groups we were able to show that indeed it's possible and we developed from the paper that was published in 2014 a principle which we now call microbial metabolite mimicry. So this a twist on an old concept but it is a new concept because we've known for decades that microbial metabolites form by bacteria and this is particularly relevant to the gut but again as I'll say it's relevant to really any organ system skin, nears, eyes wherever bacteria in the host coexist there's going to be an exchange of these chemical compounds right. So in the intestine we were able to show that indeed there are a panoply of these metabolites and they probably have different receptor systems that they bind to but no one to this date had shown that you can actually effectively make a analogue of the metabolite that had increased potency as well as remarkable safety right because it was mirroring the parent metabolite there was very little chemical change made that would give it new liabilities the molecule new liabilities so there was very little of this that you could actually mimic the metabolite with a synthetic small molecule and get away with higher potency of effect and very little downside right very little side effect and side effect is important because these off targets they cause liabilities and clinical attrition in drug development. So it was a twist on an old concept yes because there are natural products that do this you know that's how we synthesize many of the molecules we know and use to date but this was a twist on a focus of the microbial metabolites per se that could it be done and hadn't been done it was an interesting proposal it's an obvious proposal but you know could it be done. So this year in April we published an embo molecular medicine which by the way was also featured on the cover page of the journal a metaphor of our concept that microbial metabolite mimicry actually can expand the chemical drug space repertoire and give you more opportunities to develop drugs that could potentially be more effective and safe and for that we used a variety of cell line systems and a clinical model of colitis to show that indeed we could get lead therapeutic hits that simulated what the metabolites did but with great potency and really had very little downside in terms of side effects. Now I want to caution the audience that this is just a proof of concept right it has a long way to go in there probably going to be liabilities as one develops other molecules for other metabolites and so on so forth and vice versa in our case because it's in its early stage they could certainly be liabilities as we go further and so what has to then combine some smart drug development approaches and use approaches of where these small molecule mimics could be used and that lead compound we called both fkk5 and fkk6 we focused on fkk6 just to show proof of concept I think we have to come full circle back in that we also have to recognize liabilities that may develop because we use in preclinical systems we often use rodents and it's not till a later phase that we use human material either tissues ex vivo or humanized sort of systems and so we are making a concerted effort right now to actually move this to humanized systems before we do much more in terms of admi pk docs and that kind of an approach which is more traditional to do and the reason we do that is to know whether you our data that we get from mice in any way could have any effect in humans and it's very interesting that we have now recent collaborations with exciting data which I'm not privileged to discuss at this present time but that these compounds could have considerable benefit using human systems but we need to vet that out completely so our focus really is on that to vet it out and to really understand okay what's happening there's going to be attrition in this conceptual development right not every metabolite is amenable to chemical derivation analog derivation all that stuff and it also depends on the chemistry and the chemistry has to be simple and has to be cheap there is little to add to biologics which have their own sort of expenses in making and so having another sort of chemical synthetic method that's very very expensive to create a drug that really will add to the cost of care down the road so we are also very conscious of that so any procedure that allows multiple chemical steps that are very hard to harness and very costly we try to avoid and so that's also put into the early pipeline in thinking as to what we would do so our paper actually validates we believe is the first validation of early proof of concept of microbial metabolite mimicry and we're pushing that as a conceptual advance there are many authors that have actually published in the same space in the same arena and this all goes towards that namely with the aryl hydrocarbon receptor and other similar receptor systems and so you know it opens up the Pandora's box because as we discover more host microbial metabolites using state-of-art mass proteomic approaches we will or small molecule approaches we're going to find that these metabolites eventually will have some host target or targets and that would be very very interesting to delve down further into you see if any pairings the tablite receptor pairings could have a chemical space that one could take advantage of finally our focus also is on formulations discovery and pharmacology per se not all drugs can be consumed in one route you need to have some smart thinking as to what where its biggest payload would be in the case of our compounds we are considering local regional delivery particularly for rectal and distal intestinal inflammatory bowel disease but the applications are going to be much more broad as we start opening up different diseases for example with the compound and we know the compound has a very strong effect on barrier function if that's the case and that really is the case with with human systems then there is potential for use in diseases where these disrupted barrier systems accelerate the original pathology for example and liver disease of various sorts like non-alcoholic seato hepatitis there's evidence mounting evidence that the intestinal microbes are clearly potentiators of disease progression and there are numerous examples like that where you could then use this as a soft add-on approach to tackle those types of diseases the underlying principle is that long term use of these drugs do not have liability and that is the key discovery differentiator for our molecules versus you know the traditional drug discovery approaches where you certainly get hits but you just don't know what the liabilities are as you investigate them down the road so I am not announcing that we have Pandora's box opened and solved but what I am suggesting is that this is just another avenue to look at potential molecules in the chemical space that one wouldn't consider as being very attractive because the metabolite receptor interactions often are very weak and it's not of interest you know to most pharmaceutical industry or to academic researchers who are trying to get you know sort of the holy grail high interaction high specificity the other point I'd like to make is that on the flip side right one always likes in drug development to have stable compounds compounds that are metabolically stable in the body that they don't undergo breakdown or have any reactive groups that form you know as they break down and those are very very valid points but I would say that if one completely understands a metabolically labile compound that you might have some selective advantages for those compounds in certain situations and in our case again there's evolving data that our lead compound is metabolically can be broken down with a high metabolic efficiency by the liver and we are honing down on the enzyme systems that do that but the it'll be interesting as we go forward to see whether the formed metabolites off that small molecule are indeed inert and what happens to them that does give us a selective advantage because the rapid breakdown of the parental compound when applied systemically reduces the activation of PXI in the liver and other organ systems systemically thereby reducing any liabilities vis-a-vis drug-drug interactions because PXI as I mentioned is a key regulator master regulator really of drug metabolism so you don't want other drugs to be foiled by the addition of your drug because of this mechanism so in a way you know that metabolic liability gives us that selective advantage of not having to activate PXI systemically but activate it only in the region of interest which is in the intestines where we deliver it right so all these approaches are evolving approaches they're not confirmatory at the present time they're in early stages of development but these are all considerations that we have in place before we sort of launch to the next round of investigations thank you