Biology subjects

Kadiyala, G.

Publications and source records attributed to Kadiyala, G..

8 recordsLinked to original sources

bioRxiv2023

Robust acidic pH and digestive enzyme stability of anti-SarsCov2 IgY antibodies: Implications for treatment of viral transmission thru gastrointestinal, ocular, nasal and skin tissues

There are many paths for the transmission of SarsCov2 virus. The main routes are nasal and oral and the droplets carrying the virus can also be transmitted thru ocular and skin tissues. The gastrointestinal (small intestine), nasal, ocular and skin tissues all present an acidic pH milieu and therefore any treatment with antibodies thru these routes has to have the antibodies remain active at acid pH as well as be resistant to typical protease digestion. To this end we profiled our anti-SarasCov2 receptor binding domain IgY antibodies for retention of activity at acidic and basic pHs and trypsin digestion. We find that the IgY are strongly resistant to denaturation at acid pH as well as not digested by trypsin. Our data strongly support the use of these IgY in treatment of viral transmission thru the GI, nasal, ocular and skin all tissues where the pH is acidic. We also provide an enabling platform to rapidly asses the suitability of any antibody or protein therapeutic for use at acidic pH.

pharmacology and toxicology↗

bioRxiv2023

Targeted neutralizing IgY antibodies against SGLT1 glucose transporter reduce glucose uptake and improve glycemic profile in vivo

Despite the use of several drugs available to treat type 2 diabetes, many patients are unable to reach their target fasting plasma glucose and HbA1c levels. SGLT1 is the major intestinal transport transmembrane protein which functions in uptake of dietary glucose. If we antagonise the binding of dietary glucose to this transport protein, it is expected that blood glucose lowering will follow. We designed specific inhibitory avian antibodies (IgY) against the extracellular glucose binding domain of SGLT1 and tested their potential in glucose lowering. We demonstrate here the antibodies block uptake of glucose and improve the glycemic profile in vivo and represent a novel approach to inhibiting dietary glucose absorption as treatment for diabetes.

pharmacology and toxicology↗

bioRxiv2023

An Anti-diabetic Nutraceutical enhances muscle cell glucose uptake of cardiometabolic drugs

Type 2 diabetes is currently treated by multiple drugs that are often combined to achieve maximum blood glucose lowering in patients. Yet more than 50% of patients are unable to attain target glucose levels. There is clear need for agents which can be added to current drugs to help patients achieve their target blood glucose levels safely. To this end we tested an anti-diabetic nutraceutical for its ability to enhance glucose uptake in muscle cells in combination with currently used cardiometabolic drugs. We show here that the nutraceutical is able to effectively improve glucose uptake of multiple drugs suggesting that it may help in enhancement of glucose lowering by the drugs in patients and achieve optimal glucose levels.

pharmacology and toxicology↗

bioRxiv2022

Nutraceutical supplement targeting multiple molecular steps synergistically enhances muscle glucose uptake and improves in vivo oral glucose disposal

Pre diabetes and type 2 diabetes are increasingly becoming rampant world wide. While there are medications to control blood glucose in type 2 diabetics, currently there are no interventions prescribed for pre diabetes. Alternate strategies to control blood glucose are needed either to act alone in pre diabetes or as supplement to the existing drugs for type 2 diabetes. We report here the targeting of critical molecular steps in muscle glucose uptake and metabolism to result in glucose lowering using a combination of safe vitamins. Our in vitro and in vivo data support the potential for using such vitamin combination for glucose control in pre diabetes and as a supplement in type 2 diabetics.

pharmacology and toxicology↗

bioRxiv2022

A 3-Dimensional bioprinted human gut-liver axis model for studying Alcoholic Liver Disease

Gut-liver axis is the interaction between the gut, its microbiome and the liver. The crosstalk and interaction between these organs plays an important role in their individual health and disease. Alcoholic liver disease (ALD) is a case in point where dysfunction of intestine actively promotes liver damage by alcohol. A flashpoint in ALD is the breach of intestinal integrity caused by gut bacteria Enterococcus faecalis (E.Faecalis). More specifically, Cytolysin, a toxin secreted by this bacteria may have a central role in the genesis of ALD. 3-D bioprinted human simulations of the gut-liver axis may help better understand the genesis of ALD. Here we developed a 3 dimensional bioprinted in vitro model composed of human origin intestinal and liver cells to explore the role of Cytolysin and ethanol in intestinal and liver damage. We find that neither Cytolysin or ethanol are sufficient for cell damage but a combination of the two act in concert to cause maximum breach in intestinal integrity. Secondly we find that enhanced transport of macromolecules thru the intestinal layer is not caused by overt cell toxicity but occurs through potentially paracellular/transcellular pathways. Our model will be used to test repurposed and new drugs/ biologics for treatment of ALD as well as other intestinal inflammatory diseases.

pharmacology and toxicology↗

bioRxiv2022

Differential Activity of Repurposed Drugs as Receptor Binding Domain Antagonists for Omicron and Native Strains of SarsCov2

Omicron strain is the latest variant of concern of SarsCov2 virus. The mutations in this strain in the S protein Receptor Binding domain (RBD) enable it to be more transmissible as well as escape neutralizing activity by antibodies in response to vaccine. Thus, Omicron specific strategies are need to counter infection by this strain. We investigated a collection of approved drugs shown to antagonize the binding of native strain RBD to human ACE2, for their ability to antagonize binding to Omicron strain RBD. While most of the drugs the drugs that antagonize binding to native RBD are also active for Omicron RBD but some were inactive, namely drugs that contain iodine are completely inactive against Omicron RBD. Our data strongly indicate that presence of a single iodine molecule in the drug renders it inactive against Omicron strain. Thus, there is molecular specificity of drugs for antagonizing Omicron strain RBD versus native strain RBD of this virus. Such information will pave way for specific drugs for Omicron. A pragmatic message from our data is that the often-used iodine containing mouth wash and rises may be ineffective in antagonizing receptor binding of Omicron strain.

pharmacology and toxicology↗

bioRxiv2022

Edible formulations of chicken egg derived IgY antibodies neutralize SarsCoV2 Omicron RBD binding to human ACE2

SarsCoV2 virus driven pandemic continues to surge propelled by new mutations such as seen in Omicron strain. Omicron is now rapidly becoming the dominant strain globally with more than 30 mutations in the spike protein. The mutations have resulted in Omicron strain escaping most of the neutralizing antibodies generated by the current set of approved vaccines and diluting the protection offered by the vaccines and therapeutic monoclonal antibodies. This has necessitated the need for newer strategies to prevent this strain from spreading. Towards this unmet need we have developed chicken egg derived anti-RBD IgY antibodies that neutralize the binding of Omicron RBD to human ACE2. Furthermore, we have formulated the edible IgY as flavored beverages to allow for use as oral rinse and prevent the entry of Omicron in the oropharyngeal passage, a major access and accumulation point for this strain in humans.

immunology↗

bioRxiv2021

Preparation of ingestible antibodies to neutralize the binding of SarsCoV2 RBD (receptor binding domain) to human ACE2 Receptor

COVID19 continues to be a serious threat to human health and mortality. There is dire need for new solutions to combat this pandemic especially for those individuals who are not vaccinated or unable to be vaccinated and continue to be exposed to the SARSCoV2. In addition, the emergence of new more transmissible variants such as delta pose additional threat from this virus. To explore another solution for prevention and treatment of COVID 19, we have produced chicken egg derived IgY antibodies against the Receptor binding domain (RBD) of SARSCoV2 spike protein which is involved in binding to human cell ACE2 receptors. The - RBD IgY effectively neutralize the binding of RBD to ACE2 and prevent pseudovirus entry in a PRNT assay. Importantly our anti-RBD IgY also neutralize the binding of Sars CoV2 delta variant RBD to ACE2. Given that chicken egg derived IgY are safe and permissible for human consumption, we plan to develop these ingestible antibodies for prevention of viral entry in the oropharyngeal and digestive tract in humans as passive immunotherapy.

immunology↗