Krishna Kumar

Tufts University

Date: Monday, June 13, 2022
Talk Time: 05:10 pm - 05:30 pm
Talk Title: Molecular Design of Peptide Therapeutics for Silent Pandemics

Professor Kumar and his group are involved in areas of research that lie at the interface of chemistry and biology. The main goal of the research is to use chemical and biological methods to create novel and functional molecules that allows us to understand the mechanism of, and/or control biological processes. His group uses the traditional techniques of organic chemistry, such as synthesis and spectroscopy, of biological chemistry, such as recombinant DNA technology, protein purification and enzyme kinetics, and of biophysics, including investigation of protein structure in membranes.

Current projects in his laboratory focus on: De Novo protein design and evolution; Combating bacterial resistance to antibiotics; Understanding the origin of the intron-exon gene structure of modern day enzymes; Catalysis by small molecules and peptides; and Design of membrane protein architectures for specialized functions.

Obesity, Type 2 Diabetes, T2D, and related metabolic disorders afflict hundreds of millions worldwide. State of the art treatments include analogues of the endogenous gut peptide hormones called "incretins." The two principal peptides that form this class, Glucagon-like Peptide 1, GLP-1, and Glucose-dependent Insulinotropic Peptide, GIP, stimulate their cognate receptors, GLP-1R and GIPR, in different tissues with the primary function of maintaining glucose homeostasis in addition to having neuro- and cardioprotective effects. These peptides however suffer from poor metabolic stability and are rapidly degraded by the ubiquitous serine protease, dipeptidyl peptidase IV, DPP-4.

We describe here the design and development of potent peptide analogues that are completely refractory to hydrolytic enzyme action while retaining full biological activity, potency, and efficacy. As general modulators of the gut-brain axis, these peptide hormones have also high promise for untreated neurological indications such as Alzheimer's and Parkinson's diseases, and traumatic brain injury, TBI. Furthermore, the platform allows for the design of hundreds of derivatives with the ability to tune the onset and duration of action, potency, efficacy, and providing a method for modulating gut and blood brain barrier, BBB, penetration.

This lecture will describe the fundamental design principles, molecular pharmacology and in vivo data. Some of the compounds described here rival or better the compounds used in the clinic today and could serve as a model platform for discovery of clinically relevant molecular entities.

Krishna Kumar, talk image 2

Krishna Kumar
Krishna Kumar, talk image 1
Krishna Kumar, talk image 3