Rational Design of Amphipathic α-Helical and Cyclic β-Sheet Antimicrobial Peptides: Specificity and Therapeutic Potential

Author(s):  
Wendy J. Hartsock ◽  
Robert S. Hodges
2018 ◽  
Vol 35 (16) ◽  
pp. 2713-2717 ◽  
Author(s):  
Igor E Eliseev ◽  
Ivan N Terterov ◽  
Anna N Yudenko ◽  
Olga V Shamova

Abstract Motivation The rational design of antimicrobial peptides (AMPs) with increased therapeutic potential requires deep understanding of the determinants of their activities. Inspired by the computational linguistic approach, we hypothesized that sequence patterns may encode the functional features of AMPs. Results We found that α-helical and β-sheet peptides have non-intersecting pattern sets and therefore constructed new sequence templates using only helical patterns. Designed peptides adopted an α-helical conformation upon binding to lipids, confirming that the method captures structural and biophysical properties. In the antimicrobial assay, 5 of 7 designed peptides exhibited activity against Gram(+) and Gram(–) bacteria, with most potent candidate comparable to best natural peptides. We thus conclude that sequence patterns comprise the structural and functional features of α-helical AMPs and guide their efficient design. Supplementary information Supplementary data are available at Bioinformatics online.


1993 ◽  
Vol 69 (02) ◽  
pp. 157-163 ◽  
Author(s):  
Irving Fox ◽  
Adrian Dawson ◽  
Peter Loynds ◽  
Jane Eisner ◽  
Kathleen Findlen ◽  
...  

SummaryHirulog™ (BG8967) is a direct thrombin inhibitor built by rational design using the protein hirudin as a model (Maraganore et al. [1990]; Biochemistry 29: 7095–101). In order to evaluate the therapeutic potential for hirulog in the management of thrombotic disease, the tolerability and anticoagulant activity of the agent were examined in a study of human volunteers.In a randomized, placebo-controlled study (n = 54), the intravenous infusion of hirulog over 15 min showed a rapid, dose-dependent prolongation of activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). There was a corresponding dose-dependent increase in plasma hirulog levels. The peptide was rapidly cleared with a half-life of 36 min and a total body clearance rate for the peptide of 0.43 1 kg−1 h−1. Similar activity was observed following subcutaneous injection but with sustained pharmacodynamic and pharmacokinetic behavior. There was a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous (r = 0.8, p <0.001) and subcutaneous administration (r = 0.7, p = 0.002).To evaluate the possible interactions of aspirin on the tolerability and anticoagulant activity of intravenous hirulog, a cross-over design was employed in eight subjects. Aspirin administration did not modify the peptide’s activity. At the administered dose of 0.6 mg kg−1 h−1 for 2 h, hirulog infusion prolonged APTT from 230 to 260% baseline. The infusion of hirulog in subjects who had received aspirin was not associated with any significant changes in the template bleeding time.The final phase of the study examined the activity and tolerability of hirulog in ten subjects during prolonged intravenous infusions for up to 24 h. The peptide (0.3 mg kg−1 h−1) exhibited sustained anticoagulant activity with no evidence for a cumulative effect. During hirulog infusion, APTT was prolonged from 210 to 250% baseline.In all phases of the study, hirulog administration was generally well-tolerated.Our observations show that hirulog is an active antithrombin agent with excellent tolerability in humans. As a direct thrombin inhibitor, hirulog provides a novel approach for the management of thrombotic disease.


Author(s):  
Sehrish Nayab ◽  
Muhammad Aamir Aslam ◽  
Sajjad ur Rahman ◽  
Zia ud Din Sindhu ◽  
Sanaullah Sajid ◽  
...  

2016 ◽  
Vol 473 (19) ◽  
pp. 3269-3290 ◽  
Author(s):  
Neda Motamedi-Shad ◽  
Alistair M. Jagger ◽  
Maximilian Liedtke ◽  
Sarah V. Faull ◽  
Arjun Scott Nanda ◽  
...  

Serpins are important regulators of proteolytic pathways with an antiprotease activity that involves a conformational transition from a metastable to a hyperstable state. Certain mutations permit the transition to occur in the absence of a protease; when associated with an intermolecular interaction, this yields linear polymers of hyperstable serpin molecules, which accumulate at the site of synthesis. This is the basis of many pathologies termed the serpinopathies. We have previously identified a monoclonal antibody (mAb4B12) that, in single-chain form, blocks α1-antitrypsin (α1-AT) polymerisation in cells. Here, we describe the structural basis for this activity. The mAb4B12 epitope was found to encompass residues Glu32, Glu39 and His43 on helix A and Leu306 on helix I. This is not a region typically associated with the serpin mechanism of conformational change, and correspondingly the epitope was present in all tested structural forms of the protein. Antibody binding rendered β-sheet A — on the opposite face of the molecule — more liable to adopt an ‘open’ state, mediated by changes distal to the breach region and proximal to helix F. The allosteric propagation of induced changes through the molecule was evidenced by an increased rate of peptide incorporation and destabilisation of a preformed serpin–enzyme complex following mAb4B12 binding. These data suggest that prematurely shifting the β-sheet A equilibrium towards the ‘open’ state out of sequence with other changes suppresses polymer formation. This work identifies a region potentially exploitable for a rational design of ligands that is able to dynamically influence α1-AT polymerisation.


Molecules ◽  
2017 ◽  
Vol 22 (7) ◽  
pp. 1054 ◽  
Author(s):  
Anna Cirac ◽  
Maria Torné ◽  
Esther Badosa ◽  
Emilio Montesinos ◽  
Pedro Salvador ◽  
...  

Pharmaceutics ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1045
Author(s):  
Michał Burdukiewicz ◽  
Katarzyna Sidorczuk ◽  
Dominik Rafacz ◽  
Filip Pietluch ◽  
Mateusz Bąkała ◽  
...  

Antimicrobial peptides (AMPs) constitute a diverse group of bioactive molecules that provide multicellular organisms with protection against microorganisms, and microorganisms with weaponry for competition. Some AMPs can target cancer cells; thus, they are called anticancer peptides (ACPs). Due to their small size, positive charge, hydrophobicity and amphipathicity, AMPs and ACPs interact with negatively charged components of biological membranes. AMPs preferentially permeabilize microbial membranes, but ACPs additionally target mitochondrial and plasma membranes of cancer cells. The preference towards mitochondrial membranes is explained by their membrane potential, membrane composition resulting from α-proteobacterial origin and the fact that mitochondrial targeting signals could have evolved from AMPs. Taking into account the therapeutic potential of ACPs and millions of deaths due to cancer annually, it is of vital importance to find new cationic peptides that selectively destroy cancer cells. Therefore, to reduce the costs of experimental research, we have created a robust computational tool, CancerGram, that uses n-grams and random forests for predicting ACPs. Compared to other ACP classifiers, CancerGram is the first three-class model that effectively classifies peptides into: ACPs, AMPs and non-ACPs/non-AMPs, with AU1U amounting to 0.89 and a Kappa statistic of 0.65. CancerGram is available as a web server and R package on GitHub.


2020 ◽  
Vol 160 ◽  
pp. 136-169 ◽  
Author(s):  
Tetiana Melnyk ◽  
Snežana Đorđević ◽  
Inmaculada Conejos-Sánchez ◽  
María J. Vicent

2016 ◽  
Vol 14 (39) ◽  
pp. 9278-9286 ◽  
Author(s):  
G. J. Kelly ◽  
A. Foltyn-Arfa Kia ◽  
F. Hassan ◽  
S. O'Grady ◽  
M. P. Morgan ◽  
...  

The first targeted anticancer polymeric prodrug candidates of antimicrobial peptides, intended for combination therapy with another polymeric prodrug of an approved antineoplastic agent (doxorubicin) are reported.


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