The COVID-19 pandemic, caused by SARS-CoV-2, has led to substantial morbidity,
mortality, and disruption globally. Cellular entry of SARS-CoV-2 is mediated by the
viral spike protein, and affinity ligands to this surface protein have the potential for
applications as antivirals and diagnostic reagents. Here, we describe the affinity
selection of cyclic peptide ligands to the SARS-CoV-2 spike protein receptor binding
domain (RBD) from three distinct libraries (in excess of a trillion molecules each) by
mRNA display. We identified six high affinity molecules with dissociation constants
(
K
D
) in the nanomolar range (15–550 nM) to the RBD.
The highest affinity ligand could be used as an affinity reagent to detect the spike
protein in solution by ELISA, and the cocrystal structure of this molecule bound to the
RBD demonstrated that it binds to a cryptic binding site, displacing a β-strand
near the C-terminus. Our findings provide key mechanistic insight into the binding of
peptide ligands to the SARS-CoV-2 spike RBD, and the ligands discovered in this work may
find future use as reagents for diagnostic applications.
The first total synthesis of the potent anti-mycobacterial cyclic depsipeptide natural product ecumicin is described. Synthesis was achieved via a solid-phase strategy, incorporating the synthetic non-proteinogenic amino acids N-methyl-4-methoxy-l-tryptophan and threo-β-hydroxy-l-phenylalanine into the growing linear peptide chain. The synthesis employed key on-resin esterification and dimethylation steps as well as a final macrolactamization between the unusual N-methyl-4-methoxy-l-tryptophan unit and a bulky N-methyl-l-valine residue. The synthetic natural product possessed potent antimycobacterial activity against the virulent H37Rv strain of Mycobacterium tuberculosis (MIC = 312 nM).
The ohmyungsamycin ande cumicin natural product families are structurally relatedc yclic depsipeptides that display potenta ntimycobacterial activity.H erein the total syntheses of ohmyungsamycinA ,d eoxyecumicin, and ecumicin are reported, together with the direct biological comparisonof members of these naturalproduct families against Mycobacterium tuberculosis (Mtb), the etiological agento ftuberculosis (TB). The synthesis of each of the naturalp roducts employed as olid-phases trategyt oa ssemble the linear peptide precursor,i nvolving ak ey on-resin esterification and an optionalo n-resin dimethylation step, before af inal solutionphasem acrolactamization between the non-proteinogenic N-methyl-4-methoxy-l-tryptophan amino acid and ab ulky N-methyl-l-valine residue. The synthetic natural products possessed potent antimycobacteriala ctivity against Mtb with MIC 90 's ranging from 110-360 nm andr etained activity against Mtb in Mtb-infected macrophages.D eoxyecumicin also exhibitedr apid bactericidal killing against Mtb,s terilizing cultures after 21 days.
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