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Targeted Antimicrobials

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Researchers: Taylor Duvall

Targeted prodrugs

Antimicrobials, including antibiotics, antivirals, and antifungals, are effective lifesaving therapeutics against pathogenic microorganisms. As the clinical pipeline of new antimicrobials runs dry, the emergence of resistance (bacterial and viral) against existing medicines poses a serious threat to public health. There is thus an urgent need for innovative, rationally designed molecular platforms that can be rapidly developed to combat resistant strains. To combat this issue, the Alabi lab is investigating a sequence-defined oligomer scaffold (oligoTEA) as a platform for the development of antibacterial agents. The structure, hydrophobicity, and charge of oligoTEAs can be easily tailored to yield compounds with antibacterial activity at low micromolar concentrations yet very low mammalian cell toxicity. These synthetic peptide mimetics operate via membrane permeabilization, similar to natural antimicrobial peptides (e.g. polymyxins). Our current research effort is directed toward creating a synthetic targeted macromolecular prodrug that actively targets a pathogen of interest and releases a tailored membrane acting antimicrobial in the presence of host factors or virulence factors emitted by the pathogen. Our goal is to decrease the toxicity profile of the antibacterial agent while maintaining its potency.


Researchers: Anirban Das and Amitava Chandra

Fusion inhibitory lipopeptides

Viral infection of target cells occurs via the coordinated action of binding and fusion proteins. Peptides derived from the heptad repeat region of the viral fusion protein can interfere with the structural transition of the fusion protein, thus inhibiting infection at the entry stage. In a collaborative effort with the Porotto and Moscona research groups, our team collectively developed a lipopeptide inhibitory ligand that self-assembles into serum stable nanoparticles with potent antiviral activity. Self-assembly of the amphipathic lipopeptides enhances their biodistribution and half-life and contributes to enhanced in vivo efficacy. Fusion inhibitory lipopeptides are being developed agasint several viruses including Measles, Influenza, Ebola and SARS-CoV-2. Proposed anchoring of the dimeric lipopeptides against the SARS-CoV-2 virus in the host cell membrane, interactions with the viral proteins, and retention in the lungs prevented direct-contact transmission in ferrets.

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