Roles of the Conserved Amino Acid Residues in Reduced Human Defensin 5: Cysteine and Arginine Are Indispensable for Its Antibacterial Action and LPS Neutralization

Chen, Fang; Tang, Yong; Zheng, Hong; Xu, Yu; Wang, Junping

doi:10.1002/cmdc.201900282

Cited by 8 publications

(6 citation statements)

References 49 publications

(64 reference statements)

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“…Human defensins (HDs) are β-stranded peptides with evolutionarily conserved elements in the sequence. 12 We recently discovered that HD5, an intestinal AMP whose expression is increased after viral infection, 13 inhibited SARS-CoV-2 invasion by cloaking ACE2. 14 The LL37 peptide is derived from the hCAP-18 protein, which is encoded by the CAMP gene.…”

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confidence: 99%

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Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone

Wang

et al. 2021

ACS Infect. Dis.

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SARS-CoV-2 infection begins with the association of its spike 1 (S1) protein with host angiotensin-converting enzyme-2 (ACE2). Targeting the interaction between S1 and ACE2 is a practical strategy against SARS-CoV-2 infection. Herein, we show encouraging results indicating that human cathelicidin LL37 can simultaneously block viral S1 and cloak ACE2. LL37 binds to the receptor-binding domain (RBD) of S1 with high affinity (11.2 nM) and decreases subsequent recruitment of ACE2. Owing to the RBD blockade, LL37 inhibits SARS-CoV-2 S pseudovirion infection, with a half-maximal inhibitory concentration of 4.74 μg/mL. Interestingly, LL37 also binds to ACE2 with an affinity of 25.5 nM and cloaks the ligand-binding domain (LBD), thereby decreasing S1 adherence and protecting cells against pseudovirion infection in vitro . Intranasal administration of LL37 to C57 mice infected with adenovirus expressing human ACE2 either before or after pseudovirion invasion decreased lung infection. The study identified a versatile antimicrobial peptide in humans as an inhibitor of SARS-CoV-2 attachment using dual mechanisms, thus providing a potential candidate for coronavirus disease 2019 (COVID-19) prevention and treatment.

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confidence: 99%

“…Defensins and cathelicidins are two important groups of mammalian AMPs. Human defensins (HDs) are β-stranded peptides with evolutionarily conserved elements in the sequence . We recently discovered that HD5, an intestinal AMP whose expression is increased after viral infection, inhibited SARS-CoV-2 invasion by cloaking ACE2 .…”

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confidence: 99%

Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone

Wang

et al. 2021

ACS Infect. Dis.

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“…Truncated α-defensin analogues have inhibitory and killing activities against multidrug-resistant E. coli (UPEC) biofilmsin an in vitro study ( Moazzezy et al , 2020 ). The conserved cysteine and arginine residues of HD5 are indispensable for its antibacterial and LPS neutralizing effects ( Chen et al , 2019 ). In addition, the core peptide of a novel antimicrobial peptide DEFB118 significantly inhibited the mRNA levels of LPS-induced inflammatory cytokines, including IL-α, IL-1β, IL-6 and TNF-α, in RAW264.7 cells, correspondingly decreasing the secretion of IL-6 and TNF-α ( Lin et al , 2020 ; Hou et al , 2021 ).…”

Section: Host Defence By Defensins In the Reproductive Systemmentioning

confidence: 99%

Defensins: defenders of human reproductive health

Zhai

Feng

et al. 2022

Human Reproduction Update

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BACKGROUND Reproductive tract infection is an important factor leading to male and female infertility. Among female infertility factors, microbial and viral infections are the main factors affecting female reproductive health and causing tubal infertility, ectopic tubal pregnancy and premature delivery. Among male infertility factors, 13–15% of male infertility is related to infection. Defensins are cationic antibacterial and antiviral peptides, classified into α-defensins, β-defensins and θ-defensins. Humans only have α-defensins and β-defensins. Apart from their direct antimicrobial functions, defensins have an immunomodulatory function and are involved in many physiological processes. Studies have shown that defensins are widely distributed in the female reproductive tract (FRT) and male reproductive tract (MRT), playing a dual role of host defence and fertility protection. However, to our knowledge, the distribution, regulation and function of defensins in the reproductive tract and their relation to reproduction have not been reviewed. OBJECTIVE AND RATIONALE This review summarizes the expression, distribution and regulation of defensins in the reproductive tracts to reveal the updated research on the dual role of defensins in host defence and the protection of fertility. SEARCH METHODS A systematic search was conducted in PubMed using the related keywords through April 2022. Related data from original researches and reviews were integrated to comprehensively review the current findings and understanding of defensins in the human reproductive system. Meanwhile, female and male transcriptome data in the GEO database were screened to analyze defensins in the human reproductive tracts. OUTCOMES Two transcriptome databases from the GEO database (GSE7307 and GSE150852) combined with existing researches reveal the expression levels and role of the defensins in the reproductive tracts. In the FRT, a high expression level of α-defensin is found, and the expression levels of defensins in the vulva and vagina are higher than those in other organs. The expression of defensins in the endometrium varies with menstrual cycle stages and with microbial invasion. Defensins also participate in the local immune response to regulate the risk of spontaneous preterm birth. In the MRT, a high expression level of β-defensins is also found. It is mainly highly expressed in the epididymal caput and corpus, indicating that defensins play an important role in sperm maturation. The expression of defensins in the MRT varies with androgen levels, age and the status of microbial invasion. They protect the male reproductive system from bacterial infections by neutralizing lipopolysaccharide and downregulating pro-inflammatory cytokines. In addition, animal and clinical studies have shown that defensins play an important role in sperm maturation, motility and fertilization. WIDER IMPLICATIONS As a broad-spectrum antimicrobial peptide without drug resistance, defensin has great potential for developing new natural antimicrobial treatments for reproductive tract infections. However, increasing evidence has shown that defensins can not only inhibit microbial invasion but can also promote the invasion and adhesion of some microorganisms in certain biological environments, such as human immunodeficiency virus. Therefore, the safety of defensins as reproductive tract anti-infective drugs needs more in-depth research. In addition, the modulatory role of defensins in fertility requires more in-depth research since the current conclusions are based on small-size samples. At present, scientists have made many attempts at the clinical transformation of defensins. However, defensins have problems such as poor stability, low bioavailability and difficulties in their synthesis. Therefore, the production of safe, effective and low-cost drugs remains a challenge.

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“…Additionally, the shielding effects caused by high concentrations of saline and anionic proteins or nucleic acids in the serum attenuate the antibacterial activity of HD5 [ 14 ]. We previously conducted structure-activity studies on HD5 and discovered that sequence simplification by increasing the electropositive charge while simultaneously maintaining the evolutionarily conserved elements was instrumental to overcoming the molecule’s disadvantages [ 15 , 16 ]. Disulfide-stabilized natural AMPs spanning different species share a striking multidimensional signature termed the γ-core motif, which has a hallmark of GXCX 3-9 C in the sequence and consists of two antiparallel β-sheets and an interposed short turn region [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5

et al. 2022

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An increase in the number of infections caused by resistant bacteria worldwide necessitates the development of alternatives to antibiotics. Human defensin (HD) 5 is an innate immune peptide with broad-spectrum antibacterial activity, but its complicated structure makes its preparation difficult. Herein, we truncated the HD5 structure by extracting the highly conserved γ-core motif. A structure-activity study showed that this motif was ineffective in killing bacteria in the absence of specific spatial conformation. Notably, after the introduction of two intramolecular disulfide bonds, its antibacterial activity was markedly improved. Glu and Ser residues were then replaced with Arg to create the derivative RC18, which exhibited stronger potency than HD5, particularly against methicillin-resistant S. aureus (MRSA). Mechanistically, RC18 bound to lipid A and lipoteichoic acid at higher affinities than HD5. Furthermore, RC18 was more efficient than HD5 in penetrating the bacterial membranes. Molecular dynamics simulation revealed that five Arg residues, Arg1, Arg7, Arg9, Arg15, and Arg18, mediated most of the polar interactions of RC18 with the phospholipid head groups during membrane penetration. In vivo experiments indicated that RC18 decreased MRSA colonization and dramatically improved the survival of infected mice, thus demonstrating that RC18 is a promising drug candidate to treat MRSA infections.

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Roles of the Conserved Amino Acid Residues in Reduced Human Defensin 5: Cysteine and Arginine Are Indispensable for Its Antibacterial Action and LPS Neutralization

Cited by 8 publications

References 49 publications

Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone

Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone

Defensins: defenders of human reproductive health

γ-Core Guided Antibiotic Design Based on Human Enteric Defensin 5

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