Concerns in the Design and Development of Novel Antimicrobial Peptides

Parvaneh Panahi Chegini, Iraj Nikokar, Tahereh Hosseinabadi, Maryam Tabarzad

Trends in Peptide and Protein Sciences, Vol. 1 No. 4 (2017), 3 September 2017 , Page 135-143

Peptide and protein based therapeutics are the most promising approaches in today medicine. Bioactive peptides can be valuable drugs in the treatment of various illnesses, such as cardiovascular and neurodegenerative diseases. Cell toxic peptides can be considered for cancer or infection therapy. Antimicrobial peptides (AMPs) are one of the most interesting antibiotic groups in this regard, especially in drug resistance infections. Numerous AMPs have been discovered from the natural source; however, artificial synthetic ones have been also developed based on rational design or bioinformatics modeling. Physicochemical features of AMPs are highly important in their antibacterial activity as well as their toxicity. The best AMP is the one that has selective potent antimicrobial bioactivity and no or least hemolytic and cytotoxic effect. In this review, various structural factors affecting the AMPs bioactivity, such as AMPs size, charge, amphipathicity, and amino acid sequence are illustrated considering the most recently published articles. Finally, the trends in AMP design and development are discussed.



•Antimicrobial peptides are highly interesting antibiotics in multi-drug resistance infections.
•Antimicrobial peptides are short peptides with less than 50 amino acids and overall positive charge.
•First and second structural features of AMPs are important factors in their bioactivities.
•Cyclization and branching of AMPs could affect their pharmacokinetic and pharmacodynamics.

The Relationship Between Janus Kinase Pathways and MicroRNAs

Mahsa Ramezanpour, Puyan Daei, Korosh Khanaki, Tahereh Hosseinabadi, Maryam Tabarzad

Trends in Peptide and Protein Sciences, Vol. 1 No. 4 (2017), 3 September 2017 , Page 144-152

Janus Kinase (JAK) family is a group of four signaling enzymes composing of four distinct domains and involved in the intracellular pathways of cytokine downstream signaling. There are two kinase domains at C-terminal of protein, one of which is regulatory and the other has the main functionality in phosphorylation of target proteins. JAKs involve in the critical physiological processes, including immune response, growth, and differentiation. Mutations or malfunction of JAKs gene can result in pathological conditions like immuno-inflammatory diseases and malignancies. Targeting of JAK enzymes has been considered as effective therapeutic approaches in immuno-inflammatory disorders and different types of hematopoietic cancers or solid tumors. Rather than cytokines that are the natural modulators and the small chemical inhibitors developed as the therapeutic modulators of JAK enzymes, miRNAs can exert regulatory activity on JAKs. miRNAs are valuable biomarkers and regulatory elements of different pathophysiological conditions, particularly cancers. The relationships between JAK enzymes and miRNA are bi-directional, as the JAKs activity through JAK-STAT pathway as well as some other non-STAT pathways, control the expressions of various genes. These connections help scientists to design and develop novel therapeutic agents and predict the prognosis of disease following therapeutic regimens, based on these two critical components of cell biology.



•Janus kinase family consists of four signaling enzymes involved in cytokine signaling pathways.
•Modifications of JAK enzymes resulted in various pathological conditions.
•JAK2 modification is reported in several types of cancers.
•JAK modulators have been approved by FDA for treatment of several immunological and neoplastic disorders.

Evaluating the Difficulty involved in Designing Small Molecule Drugs to Inhibit Protein-Protein Interactions

Delaram Ahmadi, David Barlow

Trends in Peptide and Protein Sciences, Vol. 1 No. 4 (2017), 3 September 2017 , Page 153-166

The targeting of drugs to block protein-protein interactions (PPIs) has attracted great interest over recent years. Such targets, however, have been held to be difficult to inhibit using low molecular weight compounds, and as a consequence they are often branded as “undruggable”. This is partly because the interfaces involved are seen to be large, and the fact that they are generally regarded as being too smooth and too flat. In the work reported here, a series of quantitative systematic studies have been performed to determine the molecular area, roughness, curvature, and amino acid composition of the interfacial surfaces of PPIs, to determine the feasibility of designing small molecule drugs to inhibit these interactions. The X-ray crystal structures are analysed for a set of 48 PPIs involving G-protein, membrane receptor extracellular domain, and enzyme-inhibitor complexes. The protein partners involved in these PPIs are shown to have much larger interfacial areas than those for protein-small molecule complexes (≥ 900 Å2 vs ~250 Å2, respectively), and they have interfaces that are fairly smooth (with fractal dimensions close to 2) and quite flat (with mean surface curvatures in the order of ± 0.1 Å-1). The mean interfacial surface curvatures of the PPI protein partners, however, are seen to change upon complexation, some very significantly so. Despite the fact that the amino acid compositions of the PPI interface surfaces are found to be significantly different from that of the average protein surface (with variations according to the type of PPI), it is concluded that the prospects for designing low molecular weight PPI inhibitors that act in an orthosteric manner remain rather limited.



•Mean interfacial surface curvatures have been determined for protein-protein interaction (PPI) partners in their complexed and uncomplexed states.
•Mean interfacial surface roughnesses have been determined for protein-protein interaction (PPI) partners in their complexed and uncomplexed states.
•Amino acid compositions have been determined for PPI interface surfaces and these compared with that for the average protein surface.
•Quantification of the PPI interfacial surface properties is used to assess the druggability of these targets.

Design and Synthesis of Novel Tetrapeptide Analogues as New Cytotoxic Agents

Mohammad Ali Ahmaditaba, Mohammad Hassan Houshdar Tehrani, Afshin Zarghi, Sorayya Shahosseini, Sara Hariri

Trends in Peptide and Protein Sciences, Vol. 1 No. 4 (2017), 3 September 2017 , Page 167-176

New series of compounds based on a tetrapeptide scaffold containing methyl sulfonyl group at the para position of a phenyl ring were synthesized and their cytotoxic activities were examined against several human cancer cell lines including MCF-7 (breast cancer Cell Line), HepG2 (human liver cancer Cell Line), HT-29 (Human Colorectal Adenocarcinoma Cell Line) and A549 (adenocarcinomic human alveolar basal epithelial cells) using MTT assay. Based on the results, among the synthesized peptides, 5e, 5f, 1g, and 3g were the most potent cytotoxic compounds that were more toxic than the reference compound, Celecoxib, against the tested cell lines. These compounds could be candidate for finding cytotoxic agents with new peptide scaffolds which show COX-2 inhibitory activity as well.



•A group of tetrapeptides was reported as COX-2 inhibitors with antiproliferative activity.
•New tetrapeptides containing methyl sulfonyl group at the para position of a phenyl ring were synthesized.
•Some of novel compounds exhibited more potent cytotoxic effect than Celecoxib as the reference.

Protein Enrichment of Olive Cake Substrate by Solid State Fermentation of Lentinus edodes

Hossein Vahidi, Mahdieh Ameri Shah Reza, Farzad Kobarfard

Trends in Peptide and Protein Sciences, Vol. 1 No. 4 (2017), 3 September 2017 , Page 177-182

Solid-state fermentation technique can be used for protein enrichment of the olive cake substrate (OCS). Among microorganisms, mushrooms, in particular, white-rot fungi belonging to the genus Lentinus is known for its ability to digest the lignin and also the most effective producers of lignocellulosic enzymes. Hence, the objective of this work is to evaluate the effect of Lentinus edodes on protein content of agro by-product namely, olive cake substrate. To do so, solid state fermentation was performed at 25ºC in different conditions including various nitrogen sources, inoculum size, fermentation time, and moisture content using glass bottle as bioreactor. Protein extraction was carried out at 4ºC. The results obtained show significantly increasing protein content of OCS.



•Solid-state fermentation technique can be used for protein enrichment of the olive cake substrate (OCS).
•The nutritional value of olive cake substrate (OCS) was improved upon fungal treatment.
Lentinus edodes fungi enhanced the protein content in experimental OCS.

Study of gyrA S83R Mutation Rate in Vancomycin Resistant Entrococcus Faecium

Nasim Rahimi Rad, Seyed Kazem Bidoki, Parisa Jafari Fesharaki

Trends in Peptide and Protein Sciences, Vol. 1 No. 4 (2017), 3 September 2017 , Page 183-189

Enterococci are among Gram-positive cocci and are common inhabitants of the human gastrointestinal tract and enough potent to cause serious infections such as bacteremia, urinary tract infections (UTIs) and endocarditis. Enterococci are not generally considered as highly infectious bacterium. However, the main reason for treatment failure in enterococcal infections is acquired resistance to glycopeptide antibiotics, specifically vancomycin. Most enterococcal infections in human such as gastroenteritis, intestinal infections, and endocarditis have been caused by E. faecalis and E. facieum. They are holding the second place of most frequent cause of hospital infections since 1990. In present study gyrA S83R polymorphism rate in vancomycin resistant Enterococcus faecium isolated from environment, food industries, and hospitals of Tehran were examined by ARMS-PCR technique. DNA was extracted from the bacterial colonies using standard column method, after separating the samples into two groups of antibiotic resistant and antibiotic susceptible by antibiogram test. A fragment of gyrA gene was amplified using PCR method to investigate point mutation of S83R position. ARMS-PCR technique was applied to detect the presence or absence of mutation using a set of specified primers which can be annealed when the mutation is present. The results were statistically analyzed by chi-square test (p < 0.05) using SPSS 19th version. The results showed that there was a significant correlation between the presences of S83R polymorphism with vancomycin resistance trait in Entrococcus faecium. Therefore, this technique could be used as a diagnostic tool to detect vancomycin resistance cases of E. faecium in patients and environment.


•There is a strong association between the presence of point mutation at the position of Ser83 and vancomycin resistant phenotype.
•Resistance in Enterococcus spp. is highly mediated by mutations in gyrA gene which plays a major role in interaction with vancomycin.
•Vancomycin is the only drug that can be consistently relied on for the treatment of infections caused by multidrug resistant enterococci.
•VRE has presented a serious challenge for the Iranian medical community.