Targeting viral envelopes with antiviral peptides and peptoids and degraders, and surface proteins with small molecules

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ABSTRACT. Our overall objective is to develop a new class of direct acting-antivirals (DAAs) that can specifically target viral envelopes but not host cell membranes using our novel amphipathic, α-helical (AH) Lipid Envelope Antiviral Disruption (LEAD) peptides and peptoids (sequence-specific N-substituted glycine oligomers). Therapeutics that can specifically target enveloped viruses have the potential to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and a wide variety of RNA viruses of pandemic potential. One promising target is the lipid membrane coating that surrounds enveloped viruses, as membrane disruption can abrogate viral infectivity. This team’s investigators have developed a new class of AH peptides, and another new type of self-assembling amphipathic peptoids, that selectively form pores in high-curvature membranes such as membrane-enveloped virus particles (<160 nm diameter) but do not form pores in low-curvature membranes such as those of mammalian cells. Once a critical density of pores forms in the viral membrane, pore-induced membrane lysis occurs, leading to loss of viral infectivity. We have also showed that incorporating D-amino acids (instead of natural L-amino acids) into LEAD peptides can enhance their in vivo stability. Excitingly, our preliminary data to date showed that one LEAD peptide (AH-D) has potent antiviral activity against a wide range of enveloped viruses including Zika virus (ZIKV), Dengue virus (DENV), Chikungunya virus (CHIKV), Yellow Fever virus (YFV), Japanese encephalitis virus (JEV), and SARS-CoV-2 without cellular toxicity in vitro. Even more excitingly, when administered in vivo, AH-D peptide can protect mice against lethal ZIKV infections as well as block DENV viremia. We have also recently developed novel antiviral peptoids that can similarly target viral envelopes selectively, with potent anti-SARS-CoV-2 activity. Finally, subcutaneous administration of a LEAD peptide had reasonably comparable exposure but with a longer half-life than when administered intravenously. We now seek to advance the development of a promising lead molecule by: 1) further characterizing the biophysical properties of LEAD peptides and peptoids responsible for their antiviral activity against enveloped viruses; 2) optimizing in vivo pharmacokinetics (PK) of LEAD peptides and peptoids for subcutaneous and inhalation delivery (by collaborating with Project 2) suitable for outpatient administration; 3) evaluating antiviral efficacy of the optimized LEAD peptides and peptoids in mouse models of DENV, ZIKV, and SARS-CoV-2; and 4) nominating a top-performing LEAD peptide/peptoid for IND-enabling studies by collaborating with Project 6 on mechanisms of potential resistance to our top performing molecules, conducting synergy studies with other available DAAs including ones developed in SyneRx, and beginning initial assessments of in vitro ADME and in vivo non-GLP rat toxicity. Successful completion of our aims will yield an exciting novel class of DAAs that can specifically target viral envelopes for use alone, or in combination with other DAAs, to combat SARS-CoV-2 and other infections caused by membrane-enveloped viruses with pandemic potential.