Researchers: Meghan K. O'Leary and Taylor Duval
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 the oligoTEA scaffold as a platform for development of antibacterial agents. Recently, a library of oligoTEAs made with amino N-allyl-acrylamide monomers demonstrated antibacterial activity against MRSA, B. subtilis, VRE, and S. epidermidis. 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. Our current research effort is directed toward creating a synthetic sequence-defined macromolecular prodrug that actively targets a pathogen of interest and releases a tailored antibacterial oligoTEA only in the presence of virulence factors emitted by the pathogen. This mechanism of action, similar to that used in the field of antibody-drug conjugates, should decrease the toxicity profile of the antibacterial agent while maintaining its potency.
Fusion inhibitory lipopeptides
Researchers: Anirban Das and Pavan Bangalore
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.
Christine M. Artim, Manisha Kunala, Meghan O'Leary, and Christopher A. Alabi*. PEGylated Oligothioetheramide Prodrugs Activated by Host Serum Proteases. ChemBioChem, 2021, DOI: 10.1002/cbic.202100146
Rory D. de Vries, Katharina S. Schmitz, Francesca T. Bovier, Camilla Predella, Jonathan Khao, Danny Noack, Bart L. Haagmans, Sander Herfst, Kyle N. Stearns, Jennifer Drew-Bear, Sudipta Biswas, Barry Rockx, Gaël McGill, N. Valerio Dorrello, Samuel H. Gellman, Christopher A. Alabi*, Rik L. de Swart*, Anne Moscona*, Matteo Porotto*. Intranasal fusion inhibitory lipopeptide prevents direct contact SARS-CoV-2 transmission in ferrets. Science, 2021, DOI: 10.1126/science.abf4896
Meghan O'Leary, Sabrina S. Chen, Lars F. Westblade, and Christopher A. Alabi*. Design of a PEGylated Antimicrobial Prodrug with Species-Specific Activation. Biomacromolecules, 2021, DOI: 10.1021/acs.biomac.0c01695
Artim CM, Brown JS and Alabi CA*. Biophysical Characterization of Cationic Antibacterial Oligothioetheramides. Analytical Chemistry, 2019, DOI: 10.1021/acs.analchem.8b05721
Brown JS, Mohammed ZJ, Artim CM, Thornlow DN, Hassler JF, Rigoglioso VP, Daniel S and Alabi CA*. Antibacterial isoamphipathic oligomers highlight the importance of multimeric lipid aggregation for antibacterial potency. Communications Biology, 2018, DOI: 10.1038/s42003-018-0230-4
Artim CM,Phan NN, and Alabi CA. Effect of Composition on Antibacterial Activity of Sequence-Defined Cationic OligoTEAs. ACS Infect. Dis. 2018. DOI: 10.1021/acsinfecdis.8b00079
Porel M, Thornlow DN, Phan NN and Alabi CA. Sequence-defined Bioactive Macrocycles via an Acid-catalysed Cascade Reaction, Nature Chemistry 2016. DOI: 10.1038/nchem.2508