Inhibitory mechanism of peptides with a repeating hydrophobic and hydrophilic residue pattern on interleukin-10

Abstract

Interleukin 10 (IL-10) is a cytokine that is able to downregulate inflammation. Its overexpression is directly associated with the difficulty in the clearance of chronic viral infections, such as chronic hepatitis B, hepatitis C and HIV infection, and infection-related cancer. IL-10 signaling blockade has been proposed as a promising way of clearing chronic viral infection and preventing tumor growth in animal models. Recently, we have reported that peptides with a helical repeating pattern of hydrophobic and hydrophilic residues are able to inhibit IL-10 significantly both in vitro and in vivo. 1 In this work, we seek to further study the inhibiting mechanism of these peptides using sequence-modified peptides. As evidenced by both experimental and molecular dynamics simulation in concert the N-terminal hydrophobic peptide constructed with repeating hydrophobic and hydrophilic pattern of residues is more likely to inhibit IL10. In addition, the sequence length and the ability of protonation are also important for inhibition activity.

Recent Developments and Applications of the MMPBSA Method

“…They found that the PPC binding affinity was closer to the experimental value reported by Nantermet et al ( 2003 ). For immune disorders, studies on Janus kinases (Zhang W. et al, 2016 ; Wang J. L. et al, 2017 ), interleukin 10 cytokine (Ni et al, 2017 ), and receptor-related orphan receptor-gamma-t (Wang F. F. et al, 2015 ), were reported. For inflammatory disorders, targets such as COX-2 (Chaudhary and Aparoy, 2017 ), interleukin 6 (Verma R. et al, 2016 ), toll-like receptors (Shen et al, 2016 ), human leukocyte antigen (Kongkaew et al, 2015 ), chymase enzyme (Verma et al, 2017 ), tumor necrosis factor (Ivanisenko et al, 2014 ), and Nalp3 (Sahoo et al, 2014b ) were studied.…”

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“…46 Recently, two peptides designed through computer modelling have been shown to inhibit IL-10 mediated signaling both in vitro and in vivo. [47][48][49] Temporally blocking IL-10 signaling at the time of immunization in mice does not cause an excessive inflammatory response. 50 These results argue that imiquimod may achieve better efficacy against genital warts if used together with an IL-10 inhibitor.…”

Targeting interleukin-10 signalling for cancer immunotherapy, a promising and complicated task

“…11 Vaccination with simultaneous IL-10 signaling blockade better inhibits tumor growth Immunization and simultaneously blocking IL-10 using IL-10 receptor monoclonal antibodies drastically increase vaccineinduced antigen-specific CD8 + T cell responses, regardless the immunogen is composed of virus-like particles, peptides, soluble antigens, or nucleotides (Table 1). 10,[18][19][20] The enhanced vaccineinduced T cell responses can also be achieved by using soluble IL-10 receptor, 21 peptide-based IL-10 receptor antagonist, 22,43 or oligonucleotides. 23 Subcutaneous administration of anti-IL-10 receptor antibodies together with a vaccine, instead of intraperitoneal injection of anti-IL-10 antibodies, also elicits stronger antigen-specific CD8 + T cell responses, yet at a much lower magnitude.…”