Rise of the SARS-CoV-2 Variants: can proteomics be the silver bullet?

INTRODUCTION: The challenges posed by emergent strains of SARS-CoV-2 need to be tackled by contemporary scientific approaches, with proteomics playing a significant role. AREAS COVERED: In this review, we provide a brief synthesis of the impact of proteomics technologies in elucidating disease pathogenesis and classifiers for the prognosis of COVID-19 and propose proteomics methodologies that could play a crucial role in understanding emerging variants and their altered disease pathology. From aiding the design of novel drug candidates to facilitating the identification of T cell vaccine targets, we have discussed the impact of proteomics methods in COVID-19 research. Techniques varied as mass spectrometry, single-cell proteomics, multiplexed ELISA arrays, high-density proteome arrays, surface plasmon resonance, immunopeptidomics, and in silico docking studies that have helped augment the fight against existing diseases were useful in preparing us to tackle SARS-CoV-2 variants. We also propose an action plan for a pipeline to combat emerging pandemics using proteomics technology by adopting uniform standard operating procedures and unified data analysis paradigms. EXPERT OPINION: The knowledge about the use of diverse proteomics approaches for COVID-19 investigation will provide a framework for future basic research, better infectious disease prevention strategies, improved diagnostics, and targeted therapeutics.

Synthesis, Antibacterial Activity, and Nephrotoxicity of Polymyxin B Analogues Modified at Leu-7, d-Phe-6, and the N-Terminus Enabled by S-Lipidation.

With the post-antibiotic era rapidly approaching, many have turned their attention to developing new treatments, often by structural modification of existing antibiotics. Polymyxins, a family of lipopeptide antibiotics that are used as a last line of defense in the clinic, have recently developed resistance and exhibit significant nephrotoxicity issues. Using thiol-ene chemistry, the facile preparation of six unique S-lipidated building blocks was demonstrated and used to generate lipopeptide mimetics upon incorporation into solid-phase peptide synthesis (SPPS). We then designed and synthesized 38 polymyxin analogues, incorporating these unique building blocks at the N-terminus, or to replace hydrophobic residues at positions 6 and 7 of the native lipopeptides. Several polymyxin analogues bearing one or more S-linked lipids were found to be equipotent to polymyxin, showed minimal kidney nephrotoxicity, and demonstrated activity against several World Health Organisation (WHO) priority pathogens. The S-lipidation strategy has demonstrated potential as a novel approach to prepare innovative new lipopeptide antibiotics.

Molecular Dynamics Simulation of the Interaction of Two Linear Battacin Analogs with Model Gram-Positive and Gram-Negative Bacterial Cell Membranes.

Antimicrobial peptides (AMPs) are a potential solution to the increasing threat of antibiotic resistance, but successful design of active but nontoxic AMPs requires understanding their mechanism of action. Molecular dynamics (MD) simulations can provide atomic-level information regarding how AMPs interact with the cell membrane. Here, we have used MD simulations to study two linear analogs of battacin, a naturally occurring cyclic, lipidated, nonribosomal AMP. Like battacin, these analogs are active against Gram-negative multidrug resistant and Gram-positive bacteria, but they are less toxic than battacin. Our simulations show that this activity depends upon a combination of positively charged and hydrophobic moieties. Favorable interactions with negatively charged membrane lipid head groups drive association with the membrane and insertion of hydrophobic residues, and the N-terminal lipid anchors the peptides to the membrane surface. Both effects are required for stable membrane binding.

"CLipP"ing on lipids to generate antibacterial lipopeptides.

We herein report the synthesis and biological and computational evaluation of 12 linear analogues of the cyclic lipopeptide battacin, enabled by Cysteine Lipidation on a Peptide or Amino Acid (CLipPA) technology. Several of the novel "CLipP"ed lipopeptides exhibited low micromolar MICs and MBCs against both Gram-negative and Gram-positive bacteria. The mechanism of action was then simulated with the MIC data using computational methods.