Chinese Chemical Letters  2018, Vol. 29 Issue (7): 1079-1087   PDF    
The application of sulfur-containing peptides in drug discovery
Jiaoyan Zhaoa, Xuefeng Jianga,b    
a Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China;
b State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
Abstract: In recent decades, peptides as potential drugs were more and more explored with the development of non-oral medicine. There into, sulfur-containing peptide is one of the most popular aspects in peptide drugs due to the introduction of sulfur atoms leading unique properties. The purpose of the present review is to focus on the discovery of various sulfur-containing peptides with particular emphasis on their pharmacological mechanisms. This review is organized according to the structures of the sulfurcontaining peptides.
Key words: Peptides     Disulfide     Thioether     Thiazole     Drug discovery    
1. Introduction

Peptides are composed of amino acids and linked through the peptide bonds. So far, thousands of peptides are found in living organisms and they play a vital role in organisms, such as participate and regulate the functional activities of organism. There are three sources of therapeutic peptides: 1) recombinational peptides, 2) chemosynthetic peptides, 3) natural or bioactive peptides which are produced by human, animals or plants [1, 2].

Peptides were deemed to be not the excellent drug candidates during the early years owing to their lower oral bioavailability and easily metabolized features [3]. In recent twenty years, peptides as potential drugs were more and more widely explored with the development of non-oral medicine. The development of new strategies for promoting peptide drugs' productivity and diminishing metabolism is necessary in order to explore more excellent peptide drugs in the market. In comparison with traditional smallmolecule drugs, peptide drugs have definite functional mechanisms, improved bioactivities, high specificities and lower immunogenicities. An increasing number of peptide drugs have emerged and they are used for the treatment for various diseases including cancer, hepatitis, diabetes, AIDS and so on [4]. Thereinto, sulfur-containing peptide is one of the most popular aspects due to the introduction of sulfur atom exhibiting unique properties in the peptide drugs [5, 6]. For instance, [Met5]-enkephalin was cyclized by two side chains through disulfide-bridge to gain the analogue H-Tyr-c[D-Pen-Gly-Phe-D-Pen]-OH (c[D-Pen2, D-Pen5]-enkephalin; DPDPE). A huge conformational constraint was imposed via the 14- membered ring associating with the geminal dimethyl group to make DPDPE be a more selective and potent δ-opioid receptor ligand, and it shows powerful analgesic activities, stability against proteolytic enzymes and improved permeability through the blood-brain barrier [7-10]. Contrasts with native linear angiotensin-(1–7), thioether angiotensin-(1–7) have the capacity against degradation by angiotensin-converting enzyme (ACE). The receptor interaction can be regulated by the introduction of thioetherbridges. D-Ala7, an analogue of angiotensin-(1–7), (along with D-Pro7) can serve as antagonists which cause the disappearance of agonist activity through the modification of position 7. Amazingly, even more effective angiotensin-(1–7) agonist can be given by the introduction of thioether-bridge at position 4 and 7 [11, 12]. Sulfurcontaining peptides attract much attention in the peptide chemistry community especially in the pharmacy owing to their extraordinary stability and pharmacokinetic profiles [13].

2. Peptide drugs with disulfide

The disulfide bond, one of the most momentous covalent bond exists in peptides, plays multifold roles in peptide drugs. It contributes not only to form S-S bond via the oxidation and lead the unique spatial structure, but also to improve peptides' pharmacological activities. The cyclization of peptide through the formation of disulfide bond can stabilize its secondary structure, promote its activity, selectivity, and stability against proteases. In addition, the cell permeability of peptide can also be improved by the disulfide bond which is used as reversible covalent linker [13].

The disulfide bond is the most common motif in sulfurcontaining peptide drugs. Since the 1980 s, multiple peptide drugs with disulfide bonds have been advanced into clinical therapy successively (Table 1).

Table 1
Peptide drugs with disulfide

Romidepsin (Istodax, Fig. 1) which is a disulfide-bridge cyclized peptide was isolated from Chromobacterium violaceum [13]. It was approved by FDA in 2009 for the treatment of cutaneous T-cell lymphoma since it is a potent histone deacetylase inhibitor (HDI). As a prodrug, it has a stable hydrophobic structure where the disulfide bond can be reduced to two free sulfhydryl groups by glutathione in cell and they can combine with zinc ion to block histone deacetylase (HDAC) inhibitor's activity [13, 14]. Romidepsin can catalyze deacetylation of lysine residues in histone or nonhistone, consequently regulate the expression of genes, exert effect on cell cycle arrest, differentiation and induce apoptosis [15]. The research in vitro found its inhibitory activity to the transplanted tumor cells including lung cancer, stomach cancer, and breast cancer. It could enhance the inhibition of Erlotinib to non-small cell lung cancer and also be good for the treatment of leukemia [16].

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Fig. 1. The structures of romidepsin, oxytocin, atosiban and octreotide

Oxytocin as a disulfide-bridged cyclic nonapeptide is a hypothalamic neuropeptide hormone (Fig. 1) [13]. It was discovered by Dale in 1906. Because of the peculiar structure of oxytocin neurons, oxytocin has the double action of hormone and neurotransmitter. The related research indicated that its primary role is to promote uterine smooth muscle contraction, so that it was clinically used to induce childbirth and lactation [17, 18]. The studies on oxytocin analogues indicated that the disulfide is not the essential group but the size of 20-membered ring has momentous influence on its activities which cannot be maintained by enlarging or shrinking the size of the ring [19].

Atosiban (Tractocile, Fig. 1) [20], a disulfide-bridge cyclized nonapeptide, is developed as a tocolytics by Ferring GmbH for women in preterm labor even for those having a high blood pressure and diabetes. As a representative drug of oxytocin receptor antagonist, it can not only inhibit the oxytocin-mediated release of inositol trisphosphate from the myometrial cell membrane, but also reduce the release of calcium ion stored in myometrial cells by combining with the oxytocin receptor of the myometrium cells and the decidua. As a result, it has a significant effect on relaxing the myometrium, inhibiting uterine contraction, and suppressing the oxytocin-mediated release of prostagianndins F (PGF) and prostagianndins E (PGE) from the decidua [20, 21].

Octreotide (Sandostatin, Fig. 1) [13], as a somatostatin analog, is a disulfide-bridge cyclized octapeptide. Compared to natural somatostatin, it shows not only a better activity in inhibiting the release of growth hormone, glucagon and insulin, but also a longer half-life [13, 22]. Octreotide inhibits somatotropin, gastrointestinal and pancreatic hormones by binding to the somatostatin receptors of the tumor cells or other tissue cells with high affinity and specificity. It can also achieve the hemostasis without influencing systemic hemodynamics by decreasing splanchnic blood flow and the pressure of portal veins, since it can selectively lower the pressure of portal veins, reduce the blood flow of esophageal varices and show the effect of liver hemodynamics. Thereby, it has a better therapeutic effect on the patients with cirrhosis along with hemorrhage of digestive tract [23].

Vasopressin (Pitressin, Fig. 2) [24], produced by the nucleus of the hypothalamus, is a cyclic nonapeptide consisting of a disulfide bond. It is used to treat for diabetes insipidus and esophageal variceal bleeding in the clinic owing to its contribution to the reabsorption of solute-free water and the regulation of isotonic concentration of body fluid [24-26].

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Fig. 2. The structures of vasopressin and its analogues

Desmopressin (DDAVP, Fig. 2) as an analogue of vasopressin has a better metabolic stability and preferable antidiuretic effects on account of its deaminated cysteine at position 1 and the replacement of L -arginine with D-arginine at position 8 [13]. The prolonged antidiuretic effect makes it not only be appropriate for more enuretic disorders including primary nocturnal enuresis, nocturia and central diabetes insipidus, but also avoid other concomitant pharmacological effects [27-31].

As another analogue of vasopressin, terlipressin (Glypressin, Fig. 2) is a prodrug developed by EMA in 1990 as a potent vasoconstrictor [33]. Currently, it is used for hepatorenal syndrome type 1 in certain countries including several in Europe, but it is still in the progress in Canada and USA [32]. The activity of constricting blood vessels by Renin-angiotensin-aldosterone System (RAAS) and sympathetic nervous system (SNS) can be inhibited owing to the fact that terlipressin can constrict blood vessels, transfer excess blood from splanchnic vessels to central artery [33, 34].

Nesiritide (Natrecor, Fig. 3), a recombinant human B-type natriuretic peptide (BNP), is a disulfide-containing cyclopeptide with 32 amino acids [35]. Similar to endogenous BNP in actions, it combines with the receptors of vascular smooth muscle and guanylate cyclase of endotheliocyte which can active cyclic guanosine monophosphate (cGMP), promote vasodilation, lower arterial pressure, and increase both cardiac output and stroke volume. Meanwhile, it is effective in diuresis, the decrease of aldosterone and norepinephrine. It can also inhibit the secretion of renin and endothelin commendably [36].

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Fig. 3. The amino acid sequences of nesiritide, salmon calcitonin and ziconotide

Salmon calcitonin (Miacalcic, Fig. 3), a disulfide-containing polypeptide consisting of 32 amino acids, has a much better activity and longer drug effect than human calcitonin. It can prevent the loss of bone calcium and increase the bone mass by inhibiting the activity of osteoclast and the dissolution of bone mineral. Furthermore it's beneficial for analgesia treatment and is used for the treatment of osteoporosis in the clinic [37].

Ziconotide (Prialt, Fig. 3), developed by Elan and approved by FDA and EMA in 2005, is a synthetic ω-conotoxin polypeptide. As a blocking agent for N-type calcium channel (NCC), it is much safe and effective for neurotherapeutics [38, 39]. Ziconotide consists of 25 amino acids and three disulfide bonds which determine its' pharmacological activity. These three disulfide bonds contribute to the forming of a compact rigid structure containing four asymmetrical rings. Therefore ziconotide has a high affinity when it combines with NCCs selectively to hold back the calcium influx, excitation of neurons and the release of neurotransmitter reversibly. Its' stability can be changed by oxidant or reductant in virtue of the existence of the three disulfide bonds and the methionine on position 12. Furthermore, it can be transferred directly to therapeutic target cells due to the lacking of tissue penetration which is determined by its relative size and hydrophily [40].

Lanreotide (Somatuline, Fig. 4) [41], the first somatostatin sustained-release preparation [42], is widely used in the long-term treatment of acromegalics who have arisen a poor efficacy in surgical and radiotherapy in the clinic [43]. As a long-acting octapeptide analogue of somatostatin, it was developed by IPSEN and approved by FDA in 2007. It binds to the receptors of growth hormone, glucagon somatostatin, insulin and thyroid-stimulating hormone with high affinity to block the release of hormones, and it has a much longer half-life than otreotide [41].

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Fig. 4. The structures of lanreotide, linaclotide and eptifibatide

Linaclotide (Linzess, Fig. 4) [13], which is comprised of 14 amino acids and three disulfide bonds, is a guanylate cyclase C (GC-C) receptor agonist. It was developed by Ironwood and approved by FDA in 2012 for the treatment of adult patients with chronic idiopathic constipation (CIC) and constipation-predominant irritable bowel syndrome (IBS-C). Combining with GC-C, it leads to increase concentrations of cyclic guanosine monophosphate (cGMP), and accordingly stimulates the secretion of intestinal fluid, accelerates gastrointestinal tract transit, elevates defecation frequents, reduces the sensitivity of pain-sensitive nerve to reduce pain [44, 45].

Eptifibatide (Integrilin, Fig. 4) [46], a disulfide bridge cyclized heptapeptide, was developed by COR Therapeutics and ScheringPlough and approved by FDA in 1998 for acute coronary syndromes (ACS) [47]. As an antiplatelet aggregation drug, it prevents obstruction of myocardium artery and heart attack. Its' active group is Lys-Gly-Asp which reversibly combines with platelet glycoprotein (GP) Ⅱb/Ⅲa receptors with high affinity and selectivity. Meanwhile this active group interferes with blood coagulation factor binding to these receptors [46, 48].

Etelcalcetide (Parsabiv, Fig. 5) [49], as a second calcimimetics, was developed by Amgen and approved respectively by EMA and FDA in 2016 and 2017 for the therapy of secondary hyperparathyroidism (SHPT) caused by chronic kidney disease (CKD). It is a linear peptide with a disulfide bond, and a new antagonist for calcium-sensing receptor (CaSR). It can interfere in the production and secretion of parathyroid hormone (PTH) by combining with CaSR [50, 51]. The endmost cysteine can bind to the cysteine at position 482 on the CaSR to form a disulfide bond which rises to activate CaSR thus decreasing the concentration of PTH and Ca2+ in blood [52].

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Fig. 5. The structures of etelcalcetide and setmelanotide

Setmelanotide which consists of 8 amino acids is a disulfidebridge cyclized peptide (Fig. 5) [53]. It can bind to human melanocortin 4 receptor (MC4R) with high affinity to activate MC4R efficiently. It was developed by Rhythm Pharmaceuticals for the treatment of obesity and diabetes. Clinical studies indicated that it can induce weight loss without the increasing of heart rate and blood pressure in the obese people with MC4R, yet it is still conducted in phase 3 clinical trials [54].

Pramlintide (Symlin, Fig. 6), an amylin analogue, composed of 37 amino acids and a disulfide bridge, was developed by Amylin and approved by FDA in 2005 for diabetes (type 1 and 2). It has the role of regulating blood glucose, reducing the release of postprandial glucagon and retarding gastric emptying [55].

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Fig. 6. The amino acid sequences of pramlintide and carperitide

Carperitide (Fig. 6), a recombinant human atrial natriuretic peptide, is a disulfide bridge cyclized with 28 amino acids, and it was launched in Japan in 1995 for the treatment of acute decompensated heart failure (ADHF). It has the effect on vasodilation and diuresis, simultaneously decrease cardiac preload and afterload [56, 57]. It also can inhibit neurohormonal activities including renin-angiotensin-aldosterone system (RAAS), oxidative stress, sympathetic nerve, and endothelin-1 levels in patients with heart failure (HF) [58].

Edotreotide (SomaKit TOC, Fig. 7) [59], a disulfide-bridge cyclized peptide, was developed by Advanced Accelerator Applications and approved by EMA in 2016 as a diagnosis for the detection of gastroenteropancreatic neuroendocrine tumors (GEPNET) for adult patients [59, 60].

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Fig. 7. The structures of edotreotide, lutetium(177 L u) oxodotreotide and galliumdotatate Ga-68

Lutetium (177 L u) oxodotreotide (Lutathera, Fig. 7), an analogue of somatostatin labelled by Lu-177, is developed by Advanced Accelerator Applications and approved severally by EMA in 2017 and FDA in 2018 for the treatment of gastroenteropancreatic neuroendocrine tumor (GEP-NET) of gastrointestinal pancreas. It has excellent affinity with somatostatin receptor 2 (SSRT2) [61].

Galliumdotatate Ga-68 (Netspot, Fig. 7), developed by Advanced Accelerator Applications and approved by FDA in 2016, is an analogue of somatostatin labelled by Ga-68. When alliumdotatate Ga-68 combined with the somatostatin receptors including the malignant cell, it displays a highest affinity with receptor 2. As a radioactive diagnosticum, it is used for somatostatin receptor positive neuro-endocrine tumors (NETs') for both adult and child patients [62].

3. Peptide drugs with thioether

Thioether is a vital group in the peptide drugs because of the existence of sulfur-containing amino acids, such as methionine, cysteine and glutathione. As a linkage, the thioether bridge has a better stability than the disulfide bridge and peptide bond, and this can prolong their half-life [12]. Nevertheless, the reason for most of peptide drugs containing the thioether structure is that they are composed of sulfur-containing amino acids, in which the thioether bonds are not linkages. The roles of the sulfur atom are still undefined. From 1974, the peptide drugs with thioether motifs were summarized in Table 2.

Table 2
Peptide drugs with thioether

Carbetocin (Pabal, Fig. 8) [63], used for controlling postpartum hemorrhage after delivery, is a sulfide-containing nonapeptide analogue of oxytocic. It was developed by Ferring Pharmaceuticals and used in the clinic in 1990. Contrast with oxytocin, 1) the cysteine at position 1 is replaced by the butyryl group, 2) the butyryl group at position 4 binds to the sulfydryl of cysteine at position 6 to form sulfide, 3) the hydroxyl of tyrosine was protected by the methyl group. Simultaneously the disulfide bond in oxytocin is replaced by the sulfide bond. As a result, carbetocin is such stable that it can avoid dissociation by aminopeptidase [64]. When combining with the myometrium receptor can increase the uterine tension and extend contraction time to prevent uterine atony and postpartum hemorrhage [65].

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Fig. 8. Thioether-containing peptide drugs

Pentagastrin (Peptavlon, Fig. 8) [66], an analogue of natural gastrin, is a sulfide-containing tetrapeptide, which irritates the secretion of pepsin, gastric acid and intrinsic factor. In the pentagastrin-stimulated calcitonin test it is used as a diagnostic agent [67].

Teduglutide (Gattex, Fig. 8), an analogue of glucagon-like peptide-2 (GLP-2), was developed by NPS and approved by FDA in 2012 for short bowel syndrome (SBS). At the second position of Nterminus there is a single amino acid substitution which resists enzymatic degradation via dipeptidyl peptidase Ⅳ. Clinical trials indicated that it may enhance the intestinal absorptive capacity of patients with SBS. Meanwhile, it can help elongate the intestinal mucosal villi, promote the growth of normal intestinal epithelial cells, increase their quality and lead to the increasing of intestinal absorption area [68].

Lixisenatide (Adlyxin, Fig. 8), a GLP-1 receptor agonist, is used as a drug for diabetes type 2. It is a sulfur-containing peptide which consists of 44 amino acids. Its' parmacological mechanism is the same as incretin. Lixisenatide not only stimulates the proliferation and differentiation of pancreatic β cells, increases the synthesis of insulin, but also delays gastric emptying and decreases the requirement of food. Furthermore, it has a much better selectivity for GLP-1 receptor than the human GLP-1 [69-73].

Teriparatide (Forteo, Fig. 8), an active fragment of parathyroid hormone (PTH), is the only agent so far to facilitate bone formation and metabolism, and it was developed by Eli Lilly and approved by FDA in 2002 [74]. At the first N-terminus, teriparatide and PTH have the same34aminoacids, which is the bioactive fragment.This drug is used for the treatment of osteoporosis in the clinic. The probable mechanism of action on bone is described as follows. Teriparatide binds to the receptor on the surface of osteocyte membranes and renal tubular cells, to active protein kinases 1, cyclic adenosine monophosphate andproteinkinases C.Asa consequence, it in creases the numbers of bone cells and reduces apoptosis [75-77].

Depreotide (Neospect, Fig. 8) [78], approved severally by FDA in 1999 and EMA in 2000, is a somatostatin analogue. It consists of a cyclohexapeptide which canbe recognizedby somatostatin receptor (SSTR), and a linear tetrapeptide chain that can be chelated with the metal. Compared with octreotide, it has no disulfide bond which can be reduced during labelling and has a preferable imaging quality. Depreotide is facile in labelling since the side chain can donate electron to metal, 99m Tc, as the frequently-used metal in the clinic, combines with depreotide for the diagnosis of lung cancer and nonsmall-cell lung cancer (NSCLC) [79].

4. Peptide drugs with sulfydryl

The sulfydryl group of cysteine residue is the most active group in the amino acid residue of peptides. It can participate in multiple significant physiological reactions, such as antioxidation, nitrosylation, the exchange of sulfydryl with disulfide and so on [80].

Glutathione is a tripeptide consists of L-glutamic acid, L-cysteine and glycine (Fig. 9) [81]. Under physiological conditions, there are reduced glutathione (GSH) and oxidized glutathione (GSSG) two forms, but the major is the reduced one. There is a free sulfydryl on the side chain of cysteine which is the activecenter.Consequently, GSHcan protect the free sulfydryl in important zymoproteins against be oxidized and inactivation. Binding to the free radical in the body can help to accelerate the excretion of free radicals and alleviate the damage of free radicals to crucial organs [82]. Glutathione was extensively used in the clinic. It can protect the sulfhydryl group of proteins on the red cell membrane against be oxidized and prevent hemolysis. It can also protect the hemoglobin against be oxidized to the methemoglobin, so that the ability of sustainably transporting oxygen is also in normal state. Glutathione can also play the role of neutralizing detoxification, it can combine with the toxic compounds and the heavy metal ions in the body, transform them into harmless substances.Further more the side reaction of chemotherapy of patients with malignant tumors can also be assuaged through it [83].

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Fig. 9. The structure of glutathione

5. Peptide drugs with sulfur-containing heterocycle

Sulfur-containing heterocycles in the peptide drugs are conducive to DNA-binding. Their flexibility is unique for recognition and cleavage of the second strand of DNA.

Cobicistat (Stribild, Fig. 10) [84], an analogue of ritonavir, is a thiazole-containing peptide used for the treatment of human immunodeficiency virus (HIV). It was approved respectively by FDA in 2012 and EMA in 2013. As a new-type pharamacoenhancer of lacking anti-HIV activity, it can improve pharmacokinetic parameters of anti-HIV drugs accordingly boost their efficacy. Quad, a single tablet, is made of elvitegravir, emtricitabine, tenofovir DF and cobicistat has been approved by FDA in 2012 for HIV [84]. In comparison to the last generation agent, the dose of elvitegravir is lower, and the viral suppression is enhanced while side-effects are diminished by combining with cobicistat [85].

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Fig. 10. The structures of cobicistat and icatibant

Icatibant (Firazyr, Fig. 10) is a thiophene-containing decapeptide developed by Shire and approved severally by EMA in 2008 and FDA in 2011 for the treatment of adult patients with hereditary angioedema (HAE) [86]. As one of the three drugs for HAE in USA, it can be administrated by patients themselves so that be used in critical situation. Icatibant, similar to the structure of bradykinin, is a competitive, potent and selective antagonist of bradykinin B2 receptor, it has a strong affinity to the bradykinin B2 receptor which can lower the activity of bradykinin consequently relieve the clinical symptoms of acute attack of HAE [86, 87].

Bleomycins (Fig. 11) [88], isolated from streptomyces verticillus by Umezawa, are a family of glycopeptide antibiotics consist of bithiazole [89]. Bleomycins have effective activity against germ-cell tumors, head and neck cancers, and lymphomas. Because of the low immunosuppression and myelosuppression, they have attracted more attentions [90, 91]. Nevertheless, the limitation of their therapeutic efficacy is that theycaninvolve lung fibrosis. Bleomycins can bind to transition metals and oxygen in the presence of oneelectron reductant which can make DNA cleavage. The research on abundant bleomycin analogues indicates that the bithiazole tail collaborates with the pyrimidine moiety is responsible for DNAbinding. Meanwhile the flexibility of the bithiazole assists recognition and cleavage of the second strandofDNA. The positivelycharged groups on the bithiazole tail not only cement the combination between bleomycin to DNA electrostatically, but also aid for cellular uptake since bleomycins as hydrophilic molecules are incapable of crossing cell membranes by free diffusion [88].

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Fig. 11. The structures of bleomycins and bacitracin A

Bacitracin A is a thiazoline-containing heptapeptide isolated from "Tracy I" strain of bacillus subtilis (Fig. 11) [13]. It is used for the treatment of antibiotic-associated diarrhea and vancomycinresistant E. faecium in human [92, 93].

6. Conclusion and prospect

Peptide drugs exhibit plenty of virtues in contrast to traditional small-molecular ones, yet they have certain drawbacks such as poor stability and short half-life. The introduction of sulfur atom, in particular disulfides, can promote their stability and pharmacokinetic profiles, such as the prolonged half-life and unique interaction with the corresponding receptors, etc. Meanwhile, it is an urgent necessary for the development of more oral medicines which can provide a convenient administration route. The exploitation of more effective synthetic methods is also favorable for the field. For example, the development of pre-made diaminodiacid as the sulfur-containing bridges to make the thioether peptides fully automatically on the solid phase [94, 95]. Nonetheless, not all the roles of sulfur element are pellucid, and they deserve more academic concern and research.

Acknowledgments

The authors are grateful for financial support provided by The National Key Research and Development Program of China (No. 2017YFD0200500), the National Natural Science Foundation of China (Nos. 21722202, 21672069, 21472050), S & TCSM of Shanghai (No. 18JC1415600), S & TCSM of Shanghai (No.18JC1415600), Fok Ying Tung Education Foundation (No. 141011), DFMEC (No. 20130076110023), Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning, and National Program for Support of Top-Notch Young Professionals.

References
[1]
P.W. Latham, Nat. Biotechnol. 17 (1999) 755-757. DOI:10.1038/11686
[2]
A.K. Sato, Curr. Opin. Biotechnol. 17 (2006) 638-642. DOI:10.1016/j.copbio.2006.10.002
[3]
V. Marx, Chem. Eng. News 83 (2005) 17-24. DOI:10.1021/cen-v083n048.p017
[4]
[5]
M.C. Bagley, J.W. Dale, E.A. Merritt, X. Xiong, Chem. Rev. 105 (2005) 685-714. DOI:10.1021/cr0300441
[6]
X. Just-Baringo, F. Albericio, M. Álvarez, Angew. Chem. Int. Ed. 53 (2014) 6602-6616. DOI:10.1002/anie.201307288
[7]
[8]
S.J. Weber, D.L. Greene, S.D. Sharma, et al., J. Pharmacol. Exp. Ther. 259 (1991) 1109-1117.
[9]
S.A. Williams, T.J. Abbruscato, V.J. Hruby, T.P. Davis, J. Neurochem. 66 (1996) 1289-1299.
[10]
[11]
L.D. Kluskens, S.A. Nelemans, R. Rink, et al., J. Pharmacol. Exp. Ther. 328 (2009) 849-854. DOI:10.1124/jpet.108.146431
[12]
G.N. Moll, A. Kuipers, L. de Vries, T. Bosma, R. Rink, Drug. Discov. TodayTechnol. 6 (2009) e13-e18. DOI:10.1016/j.ddtec.2009.03.001
[13]
M. Go'ngora-Benítez, J. Tulla-Puche, F. Albericio, Chem. Rev. 114 (2014) 901-926. DOI:10.1021/cr400031z
[14]
R.L. Piekarz, R. Frye, M. Turner, et al., J. Clin. Oncol. 27 (2009) 5410-5417. DOI:10.1200/JCO.2008.21.6150
[15]
J. Panicker, Z.J. Li, C. McMahon, et al., ABBV Cell Cycle 9 (2010) 1830-1838. DOI:10.4161/cc.9.9.11543
[16]
B. Coiffier, B. Pro, H.M. Prince, et al., J. Clin. Oncol. 30 (2012) 631-636. DOI:10.1200/JCO.2011.37.4223
[17]
A. Meyer-Lindenberg, G. Domes, P. Kirsch, M. Heinrichs, Nat. Rev. Neurosci. 12 (2011) 524-538. DOI:10.1038/nrn3044
[18]
M. Manning, A. Misicka, A. Olma, et al., J. Neuroendocrinol. 24 (2012) 609-628. DOI:10.1111/j.1365-2826.2012.02303.x
[19]
Q. Liu, D.M. Qian, Q.L. Liu, H. Gao, Chin. J. Pharm. Anal. 31 (2011) 609-613.
[20]
A.D. Borthwick, J. Med. Chem. 53 (2010) 6525-6538. DOI:10.1021/jm901812z
[21]
[22]
P. Hovind, L. Simonsen, Jens Bülow, Clin. Physiol. Funct. Imaging 30 (2010) 141-145. DOI:10.1111/j.1475-097X.2009.00917.x
[23]
N. Yang, H.B. Xu, Z.S. Li, G.M. Xu, New Drug Clin. Rem. 13 (1994) 31-33.
[24]
D. Gimenez, C.A. Mooney, A. Dose, et al., Org. Biomol. Chem. 15 (2017) 4086-4095. DOI:10.1039/C7OB00283A
[25]
Q. Liu, L. Zhen, H. Gao, Chin. Pharm. Aff. 31 (2017) 479-485.
[26]
M. Thibonnier, Berti-Mattera L.N., N. Dulin, D.M. Conarty, R. Mattera, Prog. Brain Res. 119 (1999) 147-161. DOI:10.1016/S0079-6123(08)61568-X
[27]
S.K. Gudlawar, N.R. Pilli, S. Siddiraju, J. Dwivedi, J. Pharm. Anal. 7 (2017) 196-202. DOI:10.1016/j.jpha.2013.11.002
[28]
P. Hilton, S.L. Stanton, Br. J. Urol. 54 (1982) 252-255. DOI:10.1111/j.1464-410X.1982.tb06969.x
[29]
L.H. Tauris, R.F. Andersen, K. Kamperis, S. Hagstroem, S. Rittig, J. Pediatr. Urol. 8 (2012) 285-290. DOI:10.1016/j.jpurol.2011.03.018
[30]
T. Nevéus, G. Läckgren, T. Tuvemo, U. Olsson, A. Stenberg, J. Urol. 162 (1999) 2136-2140. DOI:10.1016/S0022-5347(05)68142-6
[31]
[32]
[33]
K. Wiśniewski, R. Galyean, H. Tariga, et al., J. Med. Chem. 54 (2011) 4388-4398. DOI:10.1021/jm200278m
[34]
[35]
T. Sudoh, K. Kangawa, N. Minamino, H. Matsuo, Nature 322 (1988) 78-81.
[36]
[37]
K. Henriksen, I. Byrjalsen, J.R. Andersen, et al., Bone 91 (2016) 122-129. DOI:10.1016/j.bone.2016.07.019
[38]
H. Terlau, B.M. Olivera, Phsiol. Rev. 84 (2004) 41-68. DOI:10.1152/physrev.00020.2003
[39]
[40]
[41]
F. Zhao, M.L. Mab, B. Xu, Chem. Soc. Rev. 38 (2009) 883-891. DOI:10.1039/b806410p
[42]
[43]
P.H. Caron, A. Beckers, D.R. Cullen, et al., J. Clin. Endocrinol. Metab. 87 (2002) 99-104. DOI:10.1210/jcem.87.1.8153
[44]
L.R. Potter, Pharmacol. Ther. 130 (2011) 71-82. DOI:10.1016/j.pharmthera.2010.12.005
[45]
R.W. Busby, A.P. Bryant, W.P. Bartolini, et al., Eur.J.Pharmacol. 649 (2010) 328-335. DOI:10.1016/j.ejphar.2010.09.019
[46]
[47]
U. Zeymer, H. Wienbergen, Cardiovasc. Drug. Rev. 25 (2007) 301-315.
[48]
[49]
[50]
M. Cozzolino, J. Tomlinson, L. Walsh, A. Bellasi, Expert. Opin. Emerg. Drugs 20 (2015) 197-208. DOI:10.1517/14728214.2015.1018177
[51]
[52]
S.T. Alexander, T. Hunter, S. Walter, et al., Mol. Pharmacol. 88 (2015) 853-865. DOI:10.1124/mol.115.098392
[53]
D. Palmer, J.P.L. Gonçalves, L.V. Hansen, et al., J. Med. Chem. 60 (2017) 8716-8730. DOI:10.1021/acs.jmedchem.7b00353
[54]
T.H. Collet, B. Dubern, J. Mokrosinski, et al., Mol. Membrane Biol. 6 (2017) 1321-1329.
[55]
G. Ryan, T.A. Briscoe, L. Jobe, Des Drug, Dev. Ther. 2 (2008) 203-214.
[56]
F. Nomura, N. Kurobe, Y. Mori, et al., Circ. J. 72 (2008) 1777-1786. DOI:10.1253/circj.CJ-07-0760
[57]
N. Hata, Y. Seino, T. Tsutamoto, et al., Circ. J. 72 (2008) 1787-1793. DOI:10.1253/circj.CJ-08-0130
[58]
[59]
A. Henninot, J.C. Collins, J.M. Nuss, J. Med. Chem. 61 (2018) 1382-1414. DOI:10.1021/acs.jmedchem.7b00318
[60]
[61]
[62]
[63]
K. Wiśniewski, S. Alagarsamy, R. Galyean, et al., J.Med.Chem. 57 (2014) 5306-5317. DOI:10.1021/jm500365s
[64]
T. Engstrøm, T. Barth, P. Melin, H. Vilhardt, Eur. J. Pharmacol. 355 (1998) 203-210. DOI:10.1016/S0014-2999(98)00513-5
[65]
M. Boucher, C.A. Nimrod, G.F. Tawagi, et al., J. Obstet. Gynaecol. Can. 26 (2004) 481-488. DOI:10.1016/S1701-2163(16)30659-4
[66]
A. Mahindra, K. Nooney, S. Uraon, K.K. Sharma, R. Jain, RSC Adv. 3 (2013) 16810-16816. DOI:10.1039/c3ra43040e
[67]
J.M. Braganza, K. Herman, P. Hine, G. Kay, J. Physiol. 289 (1979) 9-16. DOI:10.1113/jphysiol.1979.sp012721
[68]
M.S. Mouksassi, J.F. Marier, J. Cyran, A.A. Vinks, Clin. Pharmacol. Ther. 86 (2009) 667-671. DOI:10.1038/clpt.2009.199
[69]
[70]
U. Werner, G. Haschke, A. Herling, W. Kramer, Regul. Pept. 164 (2010) 58-64. DOI:10.1016/j.regpep.2010.05.008
[71]
M. Riddle, R. Aronson, P. Home, et al., Diabetes Care 36 (2013) 2489-2496. DOI:10.2337/dc12-2454
[72]
V. Fonseca, R. Alvarado-Ruiz, D. Raccah, et al., Diabetes Care 35 (2012) 1225-1231. DOI:10.2337/dc11-1935
[73]
Y. Seino, K. Min, E. Niemoeller, A. Takami, DiabetesObes.Metab. 14 (2012) 910-917.
[74]
T.J. Martin, J.M.W. Quinn, M.T. Gillespie, et al., Ann. N. Y. Acad. Sci. 1068 (2006) 458-470. DOI:10.1196/annals.1346.043
[75]
J. Stroup, M.P. Kane, A.M. Abu-Baker, Am. J. Health. Syst. Pharm. 65 (2008) 532-539. DOI:10.2146/ajhp070171
[76]
K.T. Brixen, P.M. Christensen, C. Ejersted, B.L. Langdahl, Basic. Clin. Pharmacol. Toxicol. 94 (2004) 260-270.
[77]
M. Girotra, M.R. Rubin, J.P. Bilezikian, Rev.Endocr.Metab.Disord. 7 (2006) 113-121.
[78]
J.E. Cyr, D.A. Pearson, C.A. Nelson, et al., J. Med. Chem. 50 (2007) 4295-4303. DOI:10.1021/jm060887v
[79]
W. Xia, R.H. Hou, Z.W. Lv, et al., Chin. J. Cancer Prev. Treat. 216 (2009) 1368-1371.
[80]
[81]
K.T.G. Samarasinghe, D.N.P. Munkanatta Godage, G.C. VanHecke, Y.H. Ahn, J. Am. Chem. Soc. 136 (2014) 11566-11569. DOI:10.1021/ja503946q
[82]
[83]
[84]
[85]
A.A. Mathias, P. German, B.P. Murray, et al., Clin. Pharmacol. Ther. 87 (2010) 322-329. DOI:10.1038/clpt.2009.228
[86]
[87]
K. Bork, U. Yasothan, P. Kirkpatrick, Nat. Rev. Drug. Discov. 7 (2008) 801-802. DOI:10.1038/nrd2694
[88]
[89]
H. Umezawa, K. Maeda, T. Takeuchi, Y. Okami, J. Antibiot. (Tokyo) 19 (1966) 200-209.
[90]
D.E. Lehane, E. Hurd, M. Lane, Cancer Res. 35 (1975) 2724-2728.
[91]
S.S. Boggs, G.P. Sartiano, A. DeMezza, Cancer Res. 34 (1974) 1938-1942.
[92]
D.S. Nielsen, N.E. Shepherd, W.J. Xu, et al., Chem. Rev. 117 (2017) 8094-8128. DOI:10.1021/acs.chemrev.6b00838
[93]
M.N. Dudley, J.C. McLaughlin, G. Carrington, et al., Arch. Intern.Med. 146 (1986) 1101-1104. DOI:10.1001/archinte.1986.00360180083015
[94]
H.K. Cui, Y. Guo, Y. He, et al., Angew. Chem. Int. Ed. 52 (2013) 9558-9562. DOI:10.1002/anie.v52.36
[95]