Development of protegrins for the treatment and prevention of oral mucositis: Structure–activity relationships of synthetic protegrin analogues

Chen, Jie; Falla, Timothy J.; Liu, Hongjian; Hurst, Malinda A.; Fujii, Craig A.; Mosca, Deborah A.; Embree, Jay R.; Loury, Dana N.; Radel, Peggy A.; Chang, Ching‐Fong; Gu, Liangcai; Fiddes, John C.

doi:10.1002/1097-0282(2000)55:1<88::aid-bip80>3.3.co;2-b

Cited by 48 publications

(107 citation statements)

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“…45 In PG-1, a noncyclic, arginine-rich antimicrobial peptide whose ␤-hairpin structure resembles that of -defensins, 25,26 an arginine to lysine substitution increased its activity against Gram-negative bacteria by up to 4-fold. 46 At present, we can only speculate as to why the subtype A and C primary isolates were more resistant to RC-100 than were the other primary isolates. Table 3 shows that the affinity of retrocyclin-1 (RC-100) and RC-101 for gp120 varied as much as 25-fold.…”

Section: Discussionmentioning

confidence: 99%

RC-101, a Retrocyclin-1 Analogue with Enhanced Activity against Primary HIV Type 1 Isolates

Owen

Rudolph

Wang

et al. 2004

AIDS Research and Human Retroviruses

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Rhesus macaques express three theta-defensins (RTDs 1-3), cyclic octadecapeptides with antiviral and lectin-like properties. Corresponding theta-defensin genes exist and are expressed in humans, but a signal sequence mutation prevents the formation of mature theta-defensin peptides. Retrocyclin-1 is a theta-defensin peptide whose precursor is encoded by human theta-defensin pseudogenes. It can protect human peripheral blood lymphocytes from infection by R5 and X4 strains of HIV-1, and provides a molecular template for designing novel antiviral agents. In this study, we used JC53-BL reporter cells to assess the activity of retrocyclin-1 (RC-100) and several analogues against primary HIV-1 isolates, including R5 and R5X4 strains of subtypes A-D, CRF-01_AE, and recombinants. Each analogue differed from retrocyclin-1 by a single amino acid substitution: Gly --> Tyr in RC-106, RC-115, and RC-116, and Arg --> Lys in RC-101. Although the modification in RC-101 was chemically conservative, this peptide was significantly more potent than retrocyclin-1 across the panel of primary isolates. We performed surface plasmon resonance binding studies, using recombinant gp120 and CD4 produced in insect cells. Although RC-100 and RC-101 bound gp120 LAV/IIIB with a K(d) of 30-35 nM, they bound gp120 from CRF-01_AE strains (CM 235 and 93TH975.15) with K(d) values of 200-750 nM. Overall, our findings suggest that clade-related differences in gp120 glycosylation impact the ability of retrocyclin-1 to bind this viral glycoprotein, and modulate the peptides' ability to prevent HIV-1 infection. The performance of RC-101 suggests that additional "engineering" could further enhance the antiviral properties of theta-defensins.

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Section: Discussionmentioning

confidence: 99%

RC-101, a Retrocyclin-1 Analogue with Enhanced Activity against Primary HIV Type 1 Isolates

Owen

Rudolph

Wang

et al. 2004

AIDS Research and Human Retroviruses

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“…Many PG-1 analogues have been developed such as PG-1 (IB-200) which exhibits MIC in the range of 0.12-2.0 µg/ml against a range of Gram-positive and Gram-negative bacteria [126]. Topical administration of protegrin in a hamster model of chemotherapy-induced oral mucositis has been shown to be associated with decreased microbial burden at mucosal lesions, decreased lesion severity, and accelerated recovery [127].…”

Section: Caths As Therapeutic Agentsmentioning

confidence: 99%

“…A recently completed phase II study of topical (oral) protegrin involving 177 patients undergoing bone morrow transplantation indicated that administration of this peptide is associated with a statistically significant reduction in mucositis after transplantation and a trend toward a reduced number of febrile days [128]. Meanwhile, a phase III study of protegrin for the prevention of mucositis in patients with myeloablative chemotherapy is now underway (IntraBiotics Pharmaceuticals) [126]. Protegrins are also being evaluated as an aerosolized antimicrobial therapy for chronic respiratory infection caused by Pseudomonas in cystic fibrosis patients and patients on ventilators.…”

Section: Caths As Therapeutic Agentsmentioning

confidence: 99%

Cathelicidins, essential gene-encoded mammalian antibiotics

2002

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Cathelicidins are a class of gene-encoded antibiotics found exclusively in mammals. In vitro and in vivo studies indicate they are effector molecules of mammalian innate immunity that can provide a first line of defense against an array of micro-organisms. Additional functions are described for some members of this class of antimicrobial peptides including chemotactic activity, mitogenesis, and angiogenesis. Therefore these peptides are considered to be multifunctional effector molecules. This review discusses recent progress in cathelicidin research and the functional properties of cathelicidins. Current work in this field suggests that understanding this component of the mammalian innate immune system and related natural antibiotic peptides offer an opportunity for the development of novel therapeutic agents with which to battle the continued problem of antimicrobial resistance.

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“…In particular, A. Mor et al, reported that repeated exposure of Gram-positive bacteria towards different AMPs at sub-minimum inhibitory concentrations (MIC) did not alter the MIC value significantly for up to more than 10e15 passes of the bacterial passage [16]. With such great potential in overcoming microbial resistance, the topical applications of these peptides have gained rising attentions as there are less toxic implications in comparison to systemic applications [17,18].…”

Section: Introductionmentioning

confidence: 99%