"A ring to govern them all.A ring to find them.A ring to attract them all and tie them in darkness ".
The Lord of theRings, J.R.R.Tolkien
The reader will think that this is one more story - the nth - about the fantastic world of J.R.R.Tolkien y su celebérrima novela.But not.This story that we are going to tell you about another ring, also powerful and unique, but in which the inscription that can be read in it is another, a single enigmatic word for the majority: cyclodextrin.
This story does not pass in Middle -earth, but in Santiago de Compostela and the world in which it is based, and its characters are not hobbits, elves, orcs or magicians, but physical and chemical.Here, the enemies are not Sauron and their hordes, but the Sars-Cov-2 and its plague, the COVID-19.
This narrative, like any published history, has a title: the Lord of the Nanoanillos: Cyclodextrinas and the battle against the Sars-Cov-2.A collective work signed by scientists from the Department of Applied Physics and the Singular Center forResearch in Biological Chemistry and Molecular Materials (CIQUS) of the University of Santiago de Compostela (USC).
Inspirada en la obra deTolkien, El Señor de los NanoAnillos es una narración científica que se agarra a la ficción tolkiana para explicar el potencial de una solución molecular en forma de anillo contra la plaga que azota a la humanidad en 2020.
But before immersing ourselves in this story, it is necessary to introduce the reader in the mysterious world of cyclodextrinas. Y para ello contamos con la colaboración de una de las creadoras de El Señor de los NanoAnillos,Rebeca García Fandiño, investigadora ‘Ramón y Cajal’ del CiQUS.
THE ORIGIN
The history of the Lord of the Nanoanillos dates back to pre-covid-19 times, when humanity was free of this plague but the magicians of science already knew the power of the cyclodextrinas.And it connects with one of the most prominent members of the ‘Nanoanillos Community’, Professor Thorsteinn Loftson, to which his disciples wanted to honor for their 70th anniversary.
“Before the Pandemia for the COVID-19 we had invited us to write an article for a special number of the International Journal of Pharmaceutics, dedicated to Professor Thorsteinn Loftson on his 70th birthday.A priori, we had not thought about sending a review article, but about publishing something related to the investigation we do with the leading molecules of the article, the cyclodextrinas. Sin embargo, a raíz de la pandemia, pensamos que un artículo en donde se hiciese una revisión del uso de estas moléculas en infecciones víricas como la covid-19 podría ser de mucha más ayuda en este momento para la comunidad científica”, explicaRebeca García Fandiño.
The appearance of an evil viral force in the world-the Sars-Cov-2-moved the original idea.The Panegyric to Loftsson and the story about the research carried out in the CIQUS on these molecules was transformed into an updated article to the times of Pandemia and unusual in the world of science by its form and structure. Sus autores encontraron enTolkien la inspiración para revisar la historia de las ciclodextrinas.
“Writing review articles can sometimes be a bit tedious, so we decided to do it in a slightly different way than we are used to.These cyclodextrinas are always represented ring -shaped, are very versatile, and have an impressive "power".The connection with the lord of the rings seemed immediate to us, ”recalls García Fandiño.
The idea had it clear: to make cyclodextrinas seductive.But how?
The Ciqus researcher explains it like this: “We live in a world in which we are supersaturated with information and lack of time.We decided what movie to see, what book to read or the attention we put in a talk during the first seconds, and what does not hook us in some way we discard it because there are multiple alternatives that are waiting for us at click.Review articles are usually boring, both for which he writes them, and for the one who reads them.They do not deal with new discoveries, but to gather the existing information on a certain topic.In this case, we wanted to make an article that we enjoy writing, also thinking that many of the possible readers could also do so by reading it.Science must be exhaustive and rigorous, but it does not have to stop being fun, but quite the opposite ”.
And this was how they came up with this fantastic story about molecular rings that could save thousands of lives in the world.Its authors: Pablo F. Garrido, Martín Calvelo, Alexandre Blanco González, Uxía Veleiro, Fabián Suárez, Daniel Conde, Alfonso Cabezón, Ángel Piñeiro yRebeca García Fandiño.
The unique ring
¿Por qué son equiparables las ciclodextrinas y el Anillo Único deTolkien?Rebeca García Fandiño justifica esta comparación tanto por la estructura cíclica de estas moléculas como por el “gran poder que presentan”.
In order for the reader to understand it better, the scientist illustrates us in the properties and use of these: “Cyclodextrinas are cyclic molecules, they are always represented by ring shape, donuts, or truncated cones.They are composed of glucopyranoside units, so they are simply sugars with very special chemical and physical properties.As sugars that are, they are not toxic, so they are used in an infinity of applications, from food, pharmacy, to cosmetics, paintings, agriculture, etc..Their nature of sugars makes them soluble in water, just like a lump that dissolves in coffee, but that solubility comes basically from the outside of the ring.The interior, however, is hydrophobic (the opposite of soluble), and allows to encapsulate other molecules that do not like water, and that would be very difficult to dissolve.Thus, used as Trojan horses, they can be used, for example, to facilitate the introduction of insoluble drugs in the body, allowing their controlled release ”.
This is the scientific explanation. Ahora se une la fantástica, el por qué las ciclodextrinas son comparables al objeto mágico de la obra deTolkien: “Las ciclodextrinas, como el Anillo Único deTolkien, son capaces de ‘volver invisibles’ a otras moléculas a las que encapsulan, controlándolas o incluso a veces aumentando su poder.Another of its qualities, also related to the power ring (which was able to adapt its size with its own will adjust to the finger of its bearer or sliding from it), is that the cyclodextrinas in solution are completely flexible and adapt to the hostto which they accommodate.It can also be said that they cause the irresistible desire to possess them: the discovery of specific cyclodextrinin the exploitation of a single cyclodextrin determined ”.
‘The lords of the Nanoanillos’
Before getting into history, we also need to know who are ‘the lords of the Nanoanillos’ and who forms the ‘ring community’.
García Fandiño replies: “The scientific community that is investigating in the field of cyclodextrinas is not small.In addition to research in the academic field, with names as well known as Fraser Stoddart, Nobel Prize in Chemistry in 2016, there are a large number of companies related to research and exploitation of these molecules.Professor Thorsteinn Loftson, honored in this issue of the International Journal of Pharmaceutics, is one of ‘The best known lords’, but it is not the only one ”.
The expert clarifies that "there are a large number of researchers working in the area, mainly in the field of the pharmaceutical industry, but also in other different fields, such as food, materials, paintings, cosmetics, etc.".
"We have been studying these systems for several years from a totally different approach, using computational simulations to understand cyclodextrinas and be able to help the design of new structures with specific applications," he adds.
Now that we know the cyclodextrinas and their connection with ‘The Lord of theRings’, we can introduce ourselves in this story in seven chapters to which an introduction to the legendarium of the Lord of the Nanoanillos precedes.
PREFACE
En la introducción a este fantástico mundo, los autores nos presentan el objeto mágico, la ciclodextrina, un anillo molecular con poderes extraordinarios descubierto por los moradores delReino de la Ciencia.
“Cyclodextrinas are among the most powerful and versatile ring structures ever known.They could be considered as the equivalent at the molecular level of the mythical unique ring created in the Middle -earth, ”the authors introduce.
The history of the cyclodextrinas begins in France in 1891, when the pharmacist and chemist Antoine Villiers discovered this molecular ring through the bacterial fermentation of starch.Villiers is the first character that is presented to us in the Lord of the Nanoanillos.The Frenchman, the authors say, "played the role of the dark Lord Sauron", when isolating these cyclic oligosaccharides and forge a molecular ring with extraordinary power.
There were many men and women of science, since then, who were captivated by him, forming the ring community in laboratories throughout the planet.Among these, they cite the Austrian chemist and bacteriologist Franz Schardinger, who in the first decade of the twentieth century gave a detail description of the preparation, separation and purification of the unique ring;or the "relevant contributions to the ring community" - they say - that have made Sergey V more recently.Kurkov and Thorsteinn Loftson at the Faculty of Pharmacy of the University of Iceland.
However, for almost a century, the power of the cyclodextrinas was barely explored, until "they took off in the 1980s, when industrial production production led to its first applications in the pharmaceutical and food industries".
“Since then, these rings are among the most versatile and multifunctional molecules used in molecular research and chemical applications, playing a relevant role in different fields such as pharmacy, medicine, chemistry, material design, food orAgricultural science, ”recall the scientists of the USC, who in their introduction enumerate and describe the specific physicochemical properties of cyclodextrine - considerate the queen of molecular encapsulation - including its potential to improve the aqueous solubility of drugs and biodisponabilityOf these, or their ability to encapsulate in their cavity, transport and release in our biological system hydrophobic drugs (insoluble).
"Although it might seem, a priori, that in a war of such magnitude against highly lethal viral enemies for humans.
At this point, it is time to enter the way and explore the world of the Lord of the Nanoanillos with the synopsis of each chapter of this adventure.
Chapter 1: The encapsulant army
Como el Anillo Único deTolkien, las ciclodextrinas son capaces de “volver invisibles” a otras moléculas a las que encapsulan, formando un “ejército” para controlarlas y llevarlas al lugar en donde deben ejercer su acción.
García Fandiño recalls that one of the greatest problems of many of the drugs available in the market, including the antivirals used for COVID-19, is their low solubility in water and, therefore, its difficulty in being introduced into the body.A problem that can be solved with the use of excipients, including cyclodextrinas, which "facilitate this work".
“These excipients are sugars (therefore, harmless to the organism), and soluble (it only takes a couple of tablespoons of sugar to a coffee to check it), but they also have a ring shape.And precisely inside that ring is where the drug is accommodated, because it is protected from water, ”describes the researcher.
Used as “Trojan Horses”, cyclodextrin.
Chapter 2: Collaborative weapons
"As demonstrated with the last alliance between elves and men in response to the threat of conquest by the Dark Sauron, the union is strength, and that must be taken into account in any battle".
With these words, García Fandiño and his collaborators immerse us in the second episode of the Lord of the Nanoanillos, in which we are discovered that “the synergy between different molecules often turns out to be much more powerful than the additive effect of them applied separately".
In the case of cyclodextrinas, they remember that it has been shown that they can enhance the effect of other molecules, including monoclonal antibodies (such as todilizumab or sarilumab), as well as other proteins (such as interferons), peptides or even nucleotides usedOr they can be used in COVID-19, to improve their stability and thus enhance their activity in the fight against infection caused by SARS-COV-2 ”.
Chapter 3: Using the ring as a direct weapon
Each cyclodextrin is unique and has properties that make it different from the others, "as well as the ring coveted by Gollum upset", compare the scientists of Santiago.
In this chapter, researchers highlight that cyclodextrin.
"It has been shown that modified cyclodextrinas can act directly as broad spectrum antiviral.
Chapter 4: Sentinels to prevent invasions
This episode addresses the use of cyclodextrinas in vaccines, comparing them with surveillance and prevention agents.García Fandiño reminds us that "the production of stable vaccines for COVID-19 is a global urgency, with a large number of initiatives in progress" worldwide.
La mayoría de estos proyectos, aclara, “se basan en subunidades no vivas y tecnologías deRNAm, [ARN mensajero] que requieren componentes adyuvantes eficientes, estables y seguros para estimular la inmunidad”.
In this sense, it emphasizes that cyclodextrinas have been used and can be used in the manufacture of vaccines, “for example reducing the possibility of suffering allergic reactions, or minimizing the degradation of the inactivated virus that is introduced into some of the vaccines that are beingdeveloping ".
CAPÍTULO 5: TRATANDO DEROMPER LAS FRONTERAS DEL ENEMIGO
Sars-Cov-2 is a virus that has the capacity to protect themselves from threatening elements.
“Like many other viruses, it is composed of a membrane formed by lipids.This barrier is what protects theRNA that it contains inside and with which it infects the cells it attacks, ”describes García Fandiño, highlighting that“ the cells of our body also have a similar membrane ”.
What happens in the infection process is that "both membranes merger, and that is how the virus can introduce its genetic material into our cells to replicate," he says.
En elReino de la Ciencia se sabe que la presencia de colesterol en las membranas juega un papel muy importante en varias enfermedades, como el alzhéimer, el cáncer, la aterosclerosis, y también en la Covid-19.Well, the unique molecular ring-cyclodextrinas-have the ability to catch cholesterol and extract it from the membranes, thus affecting the merger process between our cells and those of the virus and reducing the infectivity of the SARS-COV-2.
Chapter 6: intercepting enemy messages
The information is power and, in a war, intercepting and controlling the communications of the enemy is key to the final victory.In the war that concerns us, against the SARS-COV-2 and the plague that causes, there is a fundamental tool to win the battle of information, the interferenceRNA (ARNI).
“TheRNAI was proposed in the late 1990s as a method to silence pathogens genes, including virusRNA.This technique is to use small pieces of complementaryRNAs to neutralize MRNA molecules of the virus and thus specifically inhibit their expression or genetic translation, ”details the authors of the Lord of the Nanoanillos.
The idea is simple: it would be about intercepting the message contained.
"One of the most important limitations of this technology is how to carry out the transport of the Arni -based drug to the target cell cytoplasm maintaining its integrity, since it is a highly unstable molecule," says García Fandiño.
This problem is solved with the cyclodextrinas, which “can help maintain theRNAi and‘ accompany it ’until the interception of the message,” concludes the researcher.
Chapter 7: Blood on the battlefield
We arrive at the last and most bloody episode of this story, in which the unique ring shows its power to avoid the ravages that the infection by Coronavirus Sars-Cov-2 can cause by the coagulation of the blood and the manifestation of thrombus.
Scientists remind us that in addition to symptoms that affect the respiratory system, COVID-19 has also been related to blood coagulation problems, "being coagulopathy and intravascular coagulation disseminated a characteristic sign in most deaths".
"Anticoagulant or diluent factors of blood have been recommended, such as heparin, for critical patients, although its efficacy has not yet been validated," says the researchers.
In this blender battle, cyclodextrinas also play an important role in coagulation -related treatments: “It has been shown that some cyclodextrinas are highly efficient coagulation restorative agents, so we have also included a compilation of works in this regard in this chapter”, Clarifies García Fandiño.
Epilogue 1: Helping from Compostela
Santiago de Compostela houses one of the laboratories where this molecular war is being fought. Allí, en el CiQUS, el grupo de Química Computacional dirigido porRebeca García Fandiño trabaja en el estudio de agentes antimicrobianos involucrados en cáncer e infección.In addition, through the spin off MD.Use innovations, is being investigated in the antiviral drug field with the American company Ligand Pharmaceuticals Incorporated.
What they are seeing through computational chemistry is, through computational studies, how Captisol-a cyclodextrin included in the formulation of the already popular semDesivir that markets this company (first therapeutic antiviral treatment to treat COVID-19)-encapsulates the drug in theCOVID-19 treatment.
García Fandiño details the details of this work: “When we imagine a scientist doing experiments, we visualize him wrapped in a white coat and glasses, surrounded by flasks, test tubes and probably looking through a microscope.The scene is justified in a large part of the cases, but it is far from reality when we talk about scientists who work in fields such as chemistry or computational biophysics.Being a computational scientist is not very different from being a 'classic' scientist, you spend the day doing experiments, analyzing results and contrasting hypotheses, but instead of making mixtures in a test tube under an extractor bell, you just need a computer, a data network, and a connection to a calculation center (such as CESGA, the Galicia Supercomputing Center) ”.
The researcher considers that "this is a great advantage in the situation that we are touching and, luckily, it allows us to work and do science without any of the limitations that do exist in other areas," he says in relation to mobility restrictionsand distances imposed by pandemic.
Your group uses computational tools to investigate key processes in infection and cancer at the cell membrane level.In addition, a part of his research, both at the academic level and through the MD University Spin-Off.Use innovations, it now focuses on the computational study of cyclodextrinas.
“When the Pandemia began by COVID-19, we continue with our lines of research, but we also decided to take advantage of these tools to study certain aspects of SARS-COV-2 infection in which we thought we could contribute.In collaboration with the American company Ligand Ltd, supplier of the main excipient of the semDesivir (Captisol), we are using computational simulation to try to understand and improve the process of encapsulation of this drug, ”explains García Fandiño.
The scientist tells us that "today, the process of solubilization of the semi -viring at the molecular level is an unexplored terrain, and it is necessary.
Its research mission is to deepen the knowledge of the interactions between the drug and the excipient, thus allowing to optimize the pharmaceutical formulation and reduce the dose of medication that should be administered.
Another of the projects in which they are working related to these molecules, in collaboration with the American pharmaceutical company Underdog Pharmaceuticals, is based on the use of specific cyclodextrins to eliminate toxic sterols from cell membranes, one of the causes caused by aging.
However, they recognize that they still have "much" to do, "like all humanity".
"There is a lot to do, much to understand and much to improve.But we have a lotand economic and the short times to which its development is subjected ”.
However, he is confident that “the exceptional level of coordination and collaboration that is taking place worldwide between scientists from different fields, caused by the current situation, leads to significant advances in the development of antiviral drugs, as in the knowledge of this and other diseases".
“I think that the situation caused by COVID-19 has served as a catalyst so that for the first time there are so many people working on the same subject at the same time, and in a quite coordinated way.This situation is giving worldwide, not in isolation, and this, necessarily, must cause progress faster than expected in normal conditions.Every day more things are known about the disease mechanism and its symptoms, and new discoveries are published that can move towards finding an effective treatment.I hope we soon have effective treatments that can reduce the impact of COVID-19 and I also hope that we learn to work in this way to advance the impact of other diseases, such as cancer, or aging, equal or more important thanViral infections, ”he says.
This story, therefore, does not conclude here.He will continue writing in laboratories around the world and maybe, just maybe, someone one day dares to adapt it to the cinema.He deserves it.Meanwhile, they - the scientists - will continue trying to do their job more accessible.
Epilogue 2: helping to communicate science
García Fandiño acknowledges that it was “risky to leave the conventional schemes” that are used in scientific publications to tell the history of cyclodextrinas, and confesses that they thought they could find “that the article was not accepted in its original form”.But they decided to try.
“We take care of the exhaustivity and seriousness of the data presented, so that they could not have that argument against us and we write it by doing parallelism with the novel of J.R.R.Tolkien.The reception by the editor and the reviewers was not bad, at least we understood the comments they sent us, ”he recalls.
After deciding its publication in the special dedicated to Professor Thorsteinn Loftson, "the reception is being surprisingly good"."We did not barely disseminate and very positive comments are arriving," celebrates García Fandiño, who regrets some taboos about science and scientists: "For most of the population, science is not part of what is understood byculture.Art is considered painting, sculpture, poetry, literature, classical music ..., but not Newton's laws, DNA replication or Einstein's relativity theory.In general, it is believed that the artist can see the beauty of things, while scientists disarm it and make him boring, turning science into a watertight compartment where only some 'chosen' are able to enter and wherespeaks a language that only a few scholars understand.Even a large part of scientists have that general opinion.However, this does not have to be like this".
And this scientist believes that "maintaining rigor and seriousness in research and presentation of results, science can communicate more enjoyable to what we are used to".
TO BE CONTINUE…
The Lord of the Nanoanillos has an end, and we make spoiler: the army of cyclodextrinas and drugs that transport are advancing in their fight against COVID-19.
García Fandiño and his collaborators have it clear: “More than ever, we are in a situation of subscribing a thousand times the words of the character Dual Gollum-Sméagol: 'My Treasury'” ”.
“Cyclodextrinas have properties that make them unique and can be considered a treasure for humanity.They are crucial in a large number of fields and, very special, in health.They are also our little treasure, because an important part of our research is based on these molecules.We study them, from the computational point of view, to be applied in different fields, from their use as excipients, to agents that can be used to help stop aging, ”justifies the Galician researcher.
Pero la guerra aún no se ha ganado, así que esperamos impacientes una nueva entrega en la que desde elReino de la Ciencia nos anuncien la victoria final contra el SARS-CoV-2 y su peste.
