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The use of peptide drugs has gained popularity recently. Peptides are attractive drug targets due to their high specificity and potency towards their biological targets. A drawback for peptide drugs is a lack of stability for oral delivery. Two classes of disulfide-rich peptides, conotoxins and cyclotides, have been shown to have higher stability than linear peptides thanks to their disulfide connectivity. Conotoxins are present in the venom of cone snails, a carnivorous marine mollusk that preys upon fish, worms, or other mollusks. Conotoxins are promising drugs leads with great prospects in the treatment of diseases and disorders such as chronic pain, multiple sclerosis and Parkinson’s and Alzheimer’s diseases. Cyclotides, which are cyclic cysteine knot containing peptides, isolated from the Violaceae (violet), Rubiaceae (coffee), and Cucurbitaceae (cucurbit) families and they have a wide range of biological activities, such as anti-HIV, uterotonic, and antimicrobial. P-superfamily framework IX conotoxins (C-C- C-CXC- C) contain the same cysteine framework, homologous sequences, and similar 3D structures to cyclotides. The knot containing conotoxins have been identified in several Conus species, but this work focuses on those from Conus brunneus, Conus purpurascens, and Conus gloriamaris. The cysteine knot motif of cyclotides and P-superfamily conotoxins is characterized by a cyclic backbone and six-conserved cysteine residues that form the three-disulfide bridges of the “knot”. This motif provides cyclotides and conotoxins with superior stability against thermal, chemical, and enzymatic degradation; marking them as potential frameworks for peptide drug delivery. Presented are details on the isolation of conotoxins and cyclotides, from Viola tricolor, and the characterization of their activity in the well-characterized Drosophila melanogaster giant fiber system (GFS) neuronal circuit, which contains GAP, acetylcholine, and glutamate synapses. The transcriptomes of two Conus brunneus specimens were assembled and mined for P-superfamily framework IX conotoxins. Eleven mature P-superfamily framework IX conotoxins were identified in the crude venom. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

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Cyclic dipeptides have been widely used as pharmaceutical agents due to their favourable properties and the fact that they are more stable and membrane permeable than their linear analogues. These characteristics make cyclic dipeptides attractive to protein-based drug developers (Martins & Carvalho, 2007). In this research study, the method of Milne et al. (1992) was used to synthesize the protected linear dipeptide esters. This was followed by boiling the unprotected, linear dipeptide esters under reflux in an oil bath (Sec-butanol: toluene (4:1)). This method gave good yields and pure cyclic dipeptides. Scanning electron microscopy, thermal analysis, X-ray powder diffraction and differential scanning calorimetry were used for evaluation of the physiochemical properties of the cyclic dipeptides. High-performance liquid chromatography and thin layer chromatography were used to determine the purity of the cyclic dipeptides. The structures of the cyclic dipeptides were elucidated using infrared spectroscopy, mass spectrometry, nuclear magnetic resonance spectroscopy and molecular modeling and computational chemistry. The aim of the study was to determine the possible therapeutic activity of cyclo(D-Phe-4I-Pro) and cyclo(L-Phe-4I-Pro) with regard to antimicrobial, anticancer, antidiabetes and haematological effects. Both cyclic dipeptides showed a significant growth inhibition of Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Anticancer studies showed that both cyclic dipeptides caused growth inhibition of the MCF-7, HT-29 and HeLa cancer cell lines. Both cyclic dipeptides showed no antidiabetic activity. Haematological studies revealed that both cyclic dipeptides caused a significant effect on the clotting time and platelet aggregation. They caused an increase in clotting time and also inhibited platelet aggregation.

Cyclic dipeptides have limited conformational freedom due to their diketopiperazine backbone and their small size. They are relatively simple to synthesise, making them ideal subjects for investigation into their biological effects. Cyclic dipeptides have also been known for their multitude of biological activities, including antimicrobial, anticancer and haematological properties. In this study the cyclic dipeptides, cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro), were synthesised from their corresponding linear precursors using a modified phenol-induced cyclisation procedure. The phenol induced cyclisation procedure resulted in good yields and purity of the cyclic dipeptides. Quantitative analysis and evaluation of the physiochemical properties of the cyclic dipeptides was achieved using high-performance liquid chromatography, scanning electron microscopy, thermal analysis and X-ray powder diffraction. Structural elucidation of the cyclic dipeptides was done by means of infrared spectroscopy, mass spectroscopy, nuclear magnetic resonance spectroscopy and molecular modelling. The study‟s aim was to determine the biological activity of cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro) with respect to their anticancer, antimicrobial, haematological and ant-diabetic studies. Anticancer studies revealed that cyclo(Phe-4Cl-Pro) and cyclo(D-Phe-4Cl-Pro) inhibited the growth of HeLa (cervical cancer), HT-29 (colon cancer) and MCF-7 (breast cancer) cancer cell lines. Both cyclic dipeptides also inhibited the growth of certain selected Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Although the inhibition of growth in the anticancer and antimicrobial studies was statistically significant, the clinical relevance is questionable, since the inhibition produced by both cyclic dipeptides was very limited compared to other pre-existing anticancer and antimicrobial agents. Both cyclic dipeptides caused a significant shortening of the APTT and PT clotting times and an increase in the fibrin and D-Dimer formation. Cyclo(D-Phe-4Cl-Pro) at a screening concentration of 12.5 mM and 3.125 mM, showed significant anti-platelet activity. Both cyclic dipeptides failed to produce any inhibition of the α-Glucosidase enzyme and very limited inhibition of the α-Amylase enzyme.

Thesis (Ph. D.)--School of Pharmacy. University of Missouri--Kansas City, 2007. / "A dissertation in pharmaceutical sciences and pharmacology." Advisor: Ashim K. Mitra. Typescript. Vita. Title from "catalog record" of the print edition Description based on contents viewed May 23, 2008. Includes bibliographical references (leaves 210-225). Online version of the print edition.

Although peptides and proteins are considered as lead compounds for the discovery and development of new therapeutic agents, poor metabolic and physical properties have limited their optimisation as drug candidates (Adessi & Soto, 2002). Research by medicinal chemists however, generated the discovery of structural similarities between some peptides and diketopiperazines and the common occurrence of such compounds in natural products. This discovery initiated the synthesis of diketopiperazines from amino acids in an attempt to bypass the previously mentioned limitations of using peptides as drug candidates (Dinsmore & Beshore, 2002). Diketopiperazines (DKPs) are the simplest form of cyclic dipeptides, and a class of unexplored bioactive peptides that have great potential for the future. The compounds are relatively simple to synthesise and are prevalent in nature (Prasad, 1995). The DKP backbone is rigid and therefore poses conformational constraint on the compounds. This rigidity allows for simple conformational analysis of the compounds and also gives insight into the conformational requirements for interaction with the targets involved in their biological activity. The reduced conformational freedom also increases the receptor specificity and thus the compounds are proposed to have less unfavourable effects (Anteunis, 1978). The aim of the study was to synthesise compounds that would exhibit metabolic stability, receptor specificity and enhanced lipophilicity which would increase the bioavailability of the compounds. This was to be achieved by the introduction of fluorine and chlorine elements into the DKPs. The structure of the DKPs would be altered which in turn would improve the physicochemical properties and the biological activity of the compounds (Naumann, 1999). Cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) were synthesised using the method of Milne et al. (1992) and by boiling the linear counterparts under reflux in sec-butanol-toluene. The structures of the synthesised DKPs were elucidated using mass spectrometry, nuclear magnetic resonance spectroscopy, infrared spectroscopy and molecular modeling. Qualitative analysis and evaluation of the physicochemical properties of the DKPs were performed using high-performance liquid chromatography, scanning electron microscopy, thermogravimetric analysis, differential scanning calorimetry and x-ray powder diffraction. The study aimed to determine the biological activity of cyclo(D-Phe-2Cl-Pro) and cyclo(Phe-4F-Pro) with respect to their anticancer, antimicrobial, haematological and antidiabetic effects. The anticancer results obtained indicated that the percentage inhibition produced by both DKPs were lower than those proposed by Graz et al. (2000) for proline-containing DKPs where, a greater than 50% inhibition was observed for cyclo(Phe-Pro). Antimicrobial studies revealed that both DKPs demonstrated marginal effects on Gram-positive and Gram-negative organisms but showed significant effects against C. albicans. The haematological studies revealed that cyclo(D-Phe-2Cl-Pro) at a screening concentration of 12.5 mM, significantly decreased the levels of D-dimer (P < 0.0001). The antidiabetics studies showed limited activity of the DKPs in inhibiting the activity of α-glucosidase and α-amylase enzymes.

Cyclic dipeptides are widely used as models for larger peptides because of their simplicity and limited conformational freedom. Some cyclic dipeptides have been shown to produce antiviral, antibiotic and anti-tumour activity (Milne et al., 1998). In this study the cyclic dipeptides, cyclo(Ser-Ser) and cyclo(Ser-Tyr), were synthesised from their corresponding linear precursors using a modified phenolinduced cyclisation procedure. The phenol-induced cyclisation procedure resulted in good yields and purity of the cyclic dipeptides. Quantitative analysis and evaluation of the physicochemical properties of the cyclic dipeptides was achieved by using high-performance liquid chromatography, scanning electron microscopy, thermal analysis and X-ray powder diffraction. The structures of the synthesised cyclic dipeptides were elucidated using infrared spectroscopy, mass spectrometry, nuclear magnetic resonance spectroscopy and molecular modelling. The study aimed to determine the biological activity of cyclo(Ser-Ser) and cyclo(Ser-Tyr) with respect to their anticancer, antimicrobial, haematological and cardiac effects. Anticancer studies revealed that cyclo(Ser-Ser) and cyclo(Ser- Tyr) inhibited the growth of HeLa (cervical cancer), HT-29 (colon cancer) and MCF (breast cancer) cancer cell lines. Both cyclic dipeptides also inhibited the growth of certain selected Gram-positive, Gram-negative and fungal microorganisms in the antimicrobial study. Although the inhibition of growth in the anticancer and antimicrobial studies was statistically significant, the clinical relevance is questionable, since the inhibition produced by both cyclic dipeptides was very limited compared to other pre-existing anticancer and antimicrobial agents. Cyclo(Ser-Tyr) exhibited significant activity in the haematological studies, where it increased the rate of calcium induced-coagulation, and decreased the rate of streptokinase-induced fibrinolysis. Both cyclic dipeptides, however, failed to produce any significant effects on thrombin-substrate binding and ADPinduced platelet aggregation. Cardiac studies revealed that cyclo(Ser-Ser) and especially cyclo(Ser-Tyr) reduced the heart rate, coronary flow rate and ventricular pressure of isolated rat hearts.

Thesis (Ph. D.)--Ohio State University, 2006. / Title from first page of PDF file. Includes bibliographical references (p. 90-112).

Cyclic dipeptides have been well characterized for their multitude of biological activities, including antimicrobial and anticancer activities. Cyclo(His-Gly) and cyclo(His-Ala) have also recently been shown to possess significant anticancer activity against a range of cell lines, despite the limitations of these two molecules with respect to their physicochemical properties. Low Log P results in poor cell permeability which can often be problematic for drugs with intracellular mechanisms of action. It can also results in poor biodistribution, and theoretical Log P values for cyclo(His-Gly) and cyclo(His-Ala) were extremely low making them ideal candidates for inclusion into a nanoparticulate drug delivery system. The aim of this study was therefore to formulate and evaluate liposome-encapsulated cyclic dipeptides that increase the tumour-suppressive actions of the cyclic dipeptides, while showing a high degree of specificity for tumour cells. While liposomes are relatively simple to prepare, inter batch variation, low encapsulation and poor stability are often problematic in their production and this has lead to very few liposomal products on the market. This study aimed at using a comprehensive statistical methodology in optimizing liposome formulations encapsulating cyclo(His-Gly) and cyclo(His-Ala). Initial screening of potential factors was conducted using a 25-1 fractional factorial design. This design made use of two levels for each of the five factors and abbreviated the design to minimize runs. Although not much information is provided by these types of designs, the design was sufficient in identifying two critical factors that would be studies further in a more robust design. The two factors selected, based on the screening study, were cholesterol and stearylamine content. These two factors were then used in designing a response surface methodology (RSM) design making use of a central composite rotatable vii design (CCRD) at five levels (-1.5, -1, 0, 1, 1.5) for each factor in order to better understand the design space. Various factors influenced the measured responses of encapsulation efficiency, zeta potential, polydispersity index, cellular uptake and leakage, but most notable were the adverse effects of increasing stearylamine levels on encapsulations efficiency and cholesterol levels on leakage for both cyclo(His-Gly) and cyclo(His-Ala) liposomes. Optimized formulations were derived from the data and prepared. Fair correlation between the predicted and measured responses was obtained. The cytotoxic activity of the encapsulated cyclic dipeptides were assessed against HeLa and MCF-7 cells and found to have limited improvement in activity. However, modification of the polyethylene glycol (PEG) grafted to the liposome surface in order to target folate receptors showed good benefit in significantly decreasing the IC50 values recorded in all cells lines tested, particularly low folate HeLa cells with the lowest IC50 being recorded as 0.0962 mM for folate targeted cyclo(His-Ala). The results therefore indicate that hydrophilic cyclic dipeptides are ideal candidates for inclusion into targeted drug delivery systems such as liposomes. Key words: Liposomes, cyclo(His-Gly), cyclo(His-Ala), cyclic dipeptides, HeLa, MCF-7, folate receptors, factorial design, response surface methodology (RSM), central composite rotatable design (CCRD).