(457c) Design of Targeted Antimicrobial Macromolecules

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 and nanotechnology platforms that can be rapidly developed to combat the elimination of resistant isolates. In the first part of this talk, I will describe our research effort toward creating antibody bactericide conjugates (ABCs). ABCs are targeted synthetic macromolecular prodrugs that actively target a pathogen of interest and release bactericidal macromolecules only in the presence of virulence or host factors. This mechanism of action, similar to that used in the field of antibody-drug conjugates (ADCs), should decrease the toxicity profile of the antibacterial agent while improving its potency at the infection site. ABCs can be considered a subset of ADCs, which have achieved clinical success for cancer treatment, with 11 FDA-approved ADCs available on the market and upwards of 80 in active clinical studies. I will present two unique ABCs and discuss their assembly, characterization, mechanism of action and antibacterial activity. In the second half of this talk, I will introduce the design of a fusion inhibitory lipopeptide platform with potent antiviral activity against several viruses, including Measles (MeV) and SARS-CoV-2. 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 has developed dimeric lipopeptide inhibitory ligands that self-assemble into serum stable nanoparticles with potent antiviral activity in cotton rats (MeV) and ferrets (SARS-CoV-2). I will discuss how self-assembly of the amphipathic lipopeptides enhances their biodistribution and half-life and contributes to enhanced in vivo efficacy. Proposed anchoring of the dimeric lipopeptide in the host cell membrane, interactions with the viral proteins, and lung retention will also be discussed.