Background: Nucleopeptides are chimeric compounds of biomedical importance carrying
DNA nucleobases anchored to peptide backbones with the ascertained capacity to bind nucleic
acids. However, their ability to interact with proteins involved in pathologies of social relevance
is a feature that still requires investigation. The worrying situation currently observed
worldwide for the COVID-19 pandemic urgently requires the research on novel anti-SARSCoV-
2 molecular weapons, whose discovery can be aided by in silico predictive studies.
Objective: The aim of this work is to explore by spectroscopic methods novel features of a
thymine-bearing nucleopeptide based on L-diaminopropanoic acid, including conformational aspects
as well as its ability to bind proteins, starting from bovine serum albumin (BSA) as a model
protein. Moreover, in consideration of the importance of targeting viral proteins in the current
fight against COVID-19, we evaluated in silico the interaction of the nucleopeptide with some
of the most relevant coronavirus protein targets.
Methods: First, we investigated via circular dichroism (CD) the conformational behaviour of
this thymine-bearing nucleopeptide with temperature: we observed CD spectral changes, particularly
passing from 15 to 35 °C. Scanning Electron Microscopy (SEM) analysis of the nucleopeptide
was also conducted on nucleopeptide solid samples. Additionally, CD binding and preliminary
in silico investigations were performed with BSA as a model protein. Moreover, molecular
dockings were run using as targets some of the main SARS-CoV-2 proteins.
Results: The temperature-dependent CD behaviour reflected the three-dimensional rearrangement
of the nucleopeptide at different temperatures, with higher exposure to the solvent of its
chromophores at higher temperatures compared to a more stacked structure at a low temperature.
SEM analysis of nucleopeptide samples in the solid-state showed a granular morphology,
with a low roughness and some thread structures. Moreover, we found through spectroscopic
studies that the modified peptide bound the albumin target by inducing significant changes to
the protein secondary structure.
Conclusion: CD and preliminary in silico studies suggested that the nucleopeptide bound the
BSA protein with high affinity according to different binding modes, as testified by binding energy
scores lower than -11 kcal/mol. Interestingly, a predictive study performed on 3CLpro and
other SARS-CoV-2 protein targets suggested the potential ability of the nucleopeptide to bind
with good affinity the main protease of the virus and other relevant targets, including the RNAdependent
RNA polymerase, especially when complexed with RNA, the papain-like protease,
and the coronavirus helicase at the nucleic acid binding site.