Cyclic Peptides as Competitive Inhibitors of the 3CL Protease in Human Rhinoviruses
Primary Investigator (PI) Name
Mohammad Halim
Department
CSM – Chemistry and Biochemistry
Abstract
Human rhinoviruses (HRVs) cause the most common cold and millions of infections worldwide each year, and they often exacerbate asthma, chronic obstructive pulmonary disease (COPD), and other respiratory diseases. No effective antiviral therapies exist yet. The viral 3CL protease (3CLpro), a cysteine protease required for polyprotein processing, has been recognized as a crucial therapeutic target. High specificity and low systemic toxicity make peptide-based therapeutics particularly effective, but they suffer from challenges, mainly poor metabolic stability and susceptibility to proteolysis. Cyclic peptides help remedy many of these flaws by conferring conformational rigidity, enhanced protease resistance, and improved binding affinity. We synthesized two peptide variants using solid-phase peptide synthesis (SPPS) on a Liberty Blue system with high-swelling Rink Amide resin (0.6 mmol/g, 100–200 mesh). To begin with, we synthesized the sequence SAFWQWFSKFLGR as a linear control. We subsequently performed the synthesis, including cysteine residues at each terminus to generate CSAFWQWFSKFLGRC, designed to allow for head-to-tail cyclization. After cleavage from the resin with a trifluoroacetic acid–based cocktail, peptide was precipitated in cold ether, dissolved it in acetic acid, and lyophilized it. Liquid chromatography (LC) confirmed the purity of linear and cyclic products. Mass spectrometry confirmed this linear peptide, finding peaks at m/z 553.95 ([M+3H]³⁺), 830.43 ([M+2H]²⁺), and 1660.93 ([M+H]⁺). Mass spectrometry (MS) confirmed cyclic peptide peaks at m/z 622.63 ([M+3H]³⁺), 933.43 ([M+2H]²⁺), and 1867.22 ([M+H]⁺. Future works will focus on testing the inhibition efficiency of these peptides against the 3CLpro of Rhinovirus.
Disciplines
Medicinal-Pharmaceutical Chemistry | Organic Chemistry
Cyclic Peptides as Competitive Inhibitors of the 3CL Protease in Human Rhinoviruses
Human rhinoviruses (HRVs) cause the most common cold and millions of infections worldwide each year, and they often exacerbate asthma, chronic obstructive pulmonary disease (COPD), and other respiratory diseases. No effective antiviral therapies exist yet. The viral 3CL protease (3CLpro), a cysteine protease required for polyprotein processing, has been recognized as a crucial therapeutic target. High specificity and low systemic toxicity make peptide-based therapeutics particularly effective, but they suffer from challenges, mainly poor metabolic stability and susceptibility to proteolysis. Cyclic peptides help remedy many of these flaws by conferring conformational rigidity, enhanced protease resistance, and improved binding affinity. We synthesized two peptide variants using solid-phase peptide synthesis (SPPS) on a Liberty Blue system with high-swelling Rink Amide resin (0.6 mmol/g, 100–200 mesh). To begin with, we synthesized the sequence SAFWQWFSKFLGR as a linear control. We subsequently performed the synthesis, including cysteine residues at each terminus to generate CSAFWQWFSKFLGRC, designed to allow for head-to-tail cyclization. After cleavage from the resin with a trifluoroacetic acid–based cocktail, peptide was precipitated in cold ether, dissolved it in acetic acid, and lyophilized it. Liquid chromatography (LC) confirmed the purity of linear and cyclic products. Mass spectrometry confirmed this linear peptide, finding peaks at m/z 553.95 ([M+3H]³⁺), 830.43 ([M+2H]²⁺), and 1660.93 ([M+H]⁺). Mass spectrometry (MS) confirmed cyclic peptide peaks at m/z 622.63 ([M+3H]³⁺), 933.43 ([M+2H]²⁺), and 1867.22 ([M+H]⁺. Future works will focus on testing the inhibition efficiency of these peptides against the 3CLpro of Rhinovirus.