An Overview on Antimalarial Peptides: Natural Sources, Synthetic Methodology and Biological Properties
Abstract
:1. Introduction
2. Isolation of Antimalarial Peptide
3. Synthesis of Antimalarial Peptides
3.1. Cyclopeptides
3.1.1. Mahafacyclin B
3.1.2. Aerucylamide B
3.1.3. Cyclomarin
3.1.4. Chaiyaphumine
3.1.5. Cyclopeptides Anolgs Prepared by Macrocyclization
3.1.6. Hirsutellide A and Its Analogues
3.1.7. Macrocyclization Strategies
3.2. Linear Peptides
3.2.1. Falcitidin
3.2.2. Gallinamide
3.2.3. PfSERA5 Analogs
3.2.4. Angiotensin
3.2.5. Decoralin
3.2.6. Carmabin and Dragomabin
3.3. Biology Activity of Isolated and Synthesized Compounds
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compound | Source | Reference | |
---|---|---|---|
1 | Ribifolin | Jatropha ribifolia | [3] |
2 | Hymenocardine | Hymenocardia acida | [4] |
3 | Hymenocardinol | Hymenocardia acida | |
4 | Hymenocardine N-oxide | Hymenocardia acida | |
5 | Hymenocardine-H | Hymenocardia acida | |
6 | Nummularine-R | Ziziphus oxyphylla | [5] |
7 | O-desmethylnummularine-R | Ziziphus oxyphylla | |
8 | O-desmethylnummularine-R N-oxide | Ziziphus oxyphylla | |
9 | Hemsine-A | Ziziphus oxyphylla | |
10 | Hemsine-A N-oxide | Ziziphus oxyphylla | |
11 | Ramosine-A | Ziziphus oxyphylla | |
12 | Oxyphylline-C | Ziziphus oxyphylla | |
13 | Oxyphylline-E | Ziziphus oxyphylla | |
14 | Oxyphylline-F | Ziziphus oxyphylla | |
15 | Crotamine | rattlesnake venom | [6] |
16 | Octaminomycins A | a microbial metabolite fraction library of Streptomyces sp. RK85-270 | [7] |
17 | Octaminomycins B | a microbial metabolite fraction library of Streptomyces sp. RK85-270 | |
18 | Kakeromamide B | Fijian marine cyanobacterium Moorea producens | [8] |
19 | Pipecolisporin | Nigrospora oryzae | [9] |
20 | Kosidachins A | Pochonia binensis | [10] |
21 | Kosidachins B | Pochonia binensis | |
22 | Georatusin | Geomyces auratus | [11] |
23 | Friomaramide B | Inflatella coelosphaeroide | [12] |
24 | Shagamide A | Inflatella coelosphaeroide | |
25 | Shagamide B | Inflatella coelosphaeroide | |
26 | Shagamide C | Inflatella coelosphaeroide | |
27 | Shagamide D | Inflatella coelosphaeroide | |
28 | Shagamide E | Inflatella coelosphaeroide | |
29 | Shagamide F | Inflatella coelosphaeroide | |
30 | NpCI | Nerita versicolor | [13] |
Peptide Precursor | Product | Time (Days) | Macrocycliz Yield c/Purity d (%) | Overall Yield e (%) |
---|---|---|---|---|
H-L-Cys(Trt)-Gly-L-Thr(tBu)-Gly-L-Cys(Trt)-Gly-OH | 140 | 3 | 34 a/98 | 32 |
H-L-Ser(tBu)-L-Phe-L-Cys(Trt)-L-Met-L-Cys(Trt)-Gly-OH | 141 | 3 | 38 a/85 | 31 |
H-L-Val-Ser(tBu)-L-Phe-L-Cys(Trt)-L-Ile-L-Cys(Trt)-OH | 142 | 3 | 43 a/82 | 42 |
H-L-Cys(Trt)-L-Arg(Pbf)-L-Cys(Trt)-L-Phe-L-Ser(tBu)-Gly-OH | 143 | 3 | 27 a/80 | 22 |
H-L-Cys(Trt)-L-Ile-L-Cys(Trt)-L-Phe-L-Arg(Pbf)-Gly-OH | 144 | 3 | 26 a/93 | 23 |
H-L-Cys(Trt)-L-Cys(Trt)-L-Ile-L-Phe-L-Glu(γ-tBu)-Gly-OH | 145 | 1 | 46 a/89–59 b/85 | 43 a/55 b |
H-L-Cys(Trt)-L-Cys(Trt)-L-Ile-L-Phe-L-Glu(tBu)-Gly-OH | 146 | 2 | 59 a/83 | 51 |
H-L-Ser(tBu)-L-Ile-L-Ser(tBu)-L-Phe-L-Glu(tBu)-Gly-OH | 147 | 3 | 34 a/93 | 32 |
H-L-Met-L-Phe-L-Phe-L-Glu(tBu)-L-Met-Gly-OH | 148 | 2 | 80 a/93 | 63 |
H-L-Cys(Trt)-L-Cys(Trt)-L-Phe-L-Ser(tBu)-Gly-OH | 149 | 1 | 54 a/94 | 51 |
H-L-Cys(Trt)-L-Cys(Trt)-L-Ser(tBu)-Gly-OH | 150 | 1 | 69 a/96 | 58 |
Peptide Precursor | Product | Crude Yield a/Purity b (%) | Isolated Macrocycle Yield a/Purity b (%) | Time (h) |
---|---|---|---|---|
H-Gly-L-Cys(Trt)-L-Ile-L-Cys(Trt)-L-Phe-L-Glu-OH | 151 | 68/81 | 51/95 | 16 |
H-Gly-L-Cys(Trt)-L-Cys(Trt)-L-Ile-L-Phe-L-Glu-OH | 152 | 98/72 | 63/95 | 16 |
H-Gly-L-Ser(tBu)-L-Ile-L-Ser(tBu)-L-Phe-L-Glu-OH | 153 | 63/78 | 46/93 | 16 |
H-L-Met-Gly-L-Met-L-Phe-L-Phe-L-Glu-OH | 154 | 99/83 | 80/95 | 16 |
Macrocyle Methodology A | Yield/Purity | Macrocycle Methodology B | Yield/Purity |
---|---|---|---|
155 | 59 a/85 | 78 | 51/95 |
156 | 59/83 | 79 | 63/95 |
157 | 34/93 | 80 | 46/93 |
158 | 80/93 | 81 | 80/95 |
cpd | I | II | III | X | R |
---|---|---|---|---|---|
177 | allo-Ile | D-Phe | Gly | –O– | –CH3 |
178 | Leu | D-Phe | Gly | –O– | –CH3 |
179 | Val | D-Phe | Gly | –O– | –CH3 |
180 | Gly | D-Phe | Gly | –O– | –CH3 |
181 | Ile | D-Phe | Gly | –O– | –H |
182 | Ile | D-Phe | Gly | –NH– | –CH3 |
183 | Val | D-Phe | Gly | –NH– | –CH3 |
184 | allo-Ile | D-Phe | Gly | –NH– | –CH3 |
185 | allo-Ile | D-Phe (4-Cl) | Gly | –NH– | –CH3 |
186 | allo-Ile | D-Phe (4-OCH3) | Gly | –NH– | –CH3 |
187 | allo-Ile | D-Phe | Gly | –NH– | –CH3 |
188 | allo-Ile | D-Phe | Pro | –NH– | –CH3 |
Entry | R1C(O) | R2 | Yield (%) |
---|---|---|---|
296 | Tr | 79 (from 295) | |
297 | H | 80 (from 296) | |
298 | Tr | 67 (from 295) | |
299 | H | 20 (from 298) | |
300 | H | 37 (from 295) | |
301 | H | 33 (from 295) | |
302 | Tr | 89 (from 295) | |
303 | H | 70 (from 302) |
Analogue | R2 | R1 | Yield (Based on Original Resin Loading) |
---|---|---|---|
313 | 40% (5:1 d.r.) | ||
314 | 33% (1:1 d.r.) | ||
315 | 65% (7:1 d.r.) | ||
316 | 62% (1:1 d.r.) | ||
317 | 78% (6:1 d.r.) | ||
318 | 75% (5:1 d.r.) |
cpd | R4 | R3 | R2a | R2b | Yield (%) |
---|---|---|---|---|---|
358 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH2CH(CH3)2 | –H | 99 |
359 | Me2NCH(iPr)– | –CH2-cyclohexyl | –CH2CH(CH3)2 | –H | 98 |
360 | 4-(N-Me)-piperidine– | –CH2-cyclohexyl | –CH2CH(CH3)2 | –H | 94 |
361 | 4-(N-Me)-piperidine– | –CH2CH(CH3)2 | –CH2CH(CH3)2 | –H | 99 |
362 | Me2NCH(iPr)– | –CH2Ph | –CH2CH(CH3)2 | –H | 91 |
363 | Me2NCH(iPr)– | –CH2CH2Ph | –CH2CH(CH3)2 | –H | 98 |
364 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH2CH2Ph | –H | 94 |
365 | Me2NCH(iPr)– | –CH2-cyclohexyl | –CH2CH2Ph | –H | 90 |
366 | Me2NCH(iPr)– | –CH2-cyclohexyl | –CH2-cyclohexyl | –H | 90 |
367 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH2-cyclohexyl | –H | 95 |
368 | 4-(N-Me)-piperidine– | –CH2-cyclohexyl | –CH2-cyclohexyl | –H | 81 |
369 | 4-(N-Me)-piperidine– | –CH2CH(CH3)2 | –CH2-cyclohexyl | –H | 98 |
370 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH3 | –CH3 | 93 |
cpd | R4 | R3 | R2a | R2b | R1a | R1b | Yield (%) |
---|---|---|---|---|---|---|---|
352 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH2CH(CH3)2 | –H | –CH3 | –H | 91 |
371 | Me2NCH(iPr)– | –CH2-cyclohexyl | –CH2CH(CH3)2 | –H | –CH3 | –H | 72 |
372 | 4-(N-Me)-piperidine– | –CH2-cyclohexyl | –CH2CH(CH3)2 | –H | –CH3 | –H | 86 |
373 | 4-(N-Me)-piperidine– | –CH2CH(CH3)2 | –CH2CH(CH3)2 | –H | –CH3 | –H | 78 |
374 | Me2NCH(iPr)– | –CH2Ph | –CH2CH(CH3)2 | –H | –CH3 | –H | 92 |
375 | Me2NCH(iPr)– | –CH2CH2Ph | –CH2CH(CH3)2 | –H | –CH3 | –H | 83 |
376 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH2CH2Ph | –H | –CH3 | –H | 90 |
377 | Me2NCH(iPr)– | –CH2-cyclohexyl | –CH2CH2Ph | –H | –CH3 | –H | 87 |
378 | Me2NCH(iPr)– | –CH2-cyclohexyl | –CH2-cyclohexyl | –H | –CH3 | –H | 93 |
379 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH2-cyclohexyl | –H | –CH3 | –H | 71 |
380 | 4-(N-Me)piperidine– | –CH2-cyclohexyl | –CH2-cyclohexyl | –H | –CH3 | –H | 68 |
381 | 4-(N-Me)piperidine– | –CH2CH(CH3)2 | –CH2-cyclohexyl | –H | –CH3 | –H | 95 |
382 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH3 | –CH3 | –CH3 | –H | 81 |
383 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH2CH(CH3)2 | –H | –CH3 | –CH3 | 51 a |
384 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH2CH(CH3)2 | –H | –cyclohexyl | –H | 69 |
385 | Me2NCH(iPr)– | –CH2-cyclohexyl | –CH2CH(CH3)2 | –H | –cyclohexyl | –H | 65 |
386 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH2CH(CH3)2 | –H | –CH2-cyclohexyl | –H | 88 |
387 | Me2NCH(iPr)– | –CH2CH(CH3)2 | –CH2CH(CH3)2 | –H | –CH2CH2Ph | –H | 83 |
Peptides | Amino Acid Sequence | Position | Mol. Mass (Da) |
---|---|---|---|
SE5 P1 (388) | Ac-TTKKESKIYDYYL-NH2 | 830–842 aa | 1821 |
SE5 P2 (389) | Ac-KASPEFYHNLYFKNF-NH2 | 843–857 aa | 1946 |
SE5 P3 (390) | Ac-NVGKKNLFSEKEDN-NH2 | 858–871 aa | 1663 |
SE5 P4 (391) | Ac-KKYVKLPSNGTTGEQ-NH2 | 176–190 aa | 1691 |
SE5 P5 (392) | Ac-GSSTGTVRGDTEPISDS-NH2 | 191–207 aa | 1707 |
SE5 P6 (393) | Ac-SESLPANGPDSPTVK-NH2 | 233–247 aa | 1540 |
SE5 P7 (394) | Ac-FKEIKAETEDDDEDDY-NH2 | 384–399 aa | 2003 |
SE5 P8 (395) | Ac-YIIFGQDTAGSGQSGK-NH2 | 881–896 aa | 1670 |
SE5 P9 (396) | Ac-TALESAGTSNEVSERV-NH2 | 900–915 aa | 1620 |
Entry | Name | Sequence | HPLC Purity a (%) | Calcd Mass b (g mol−1) | Obsd Mass b (g mol−1) |
---|---|---|---|---|---|
397 | [Ile6,His5]-All | DRVYHIPF | 98 | 1045.5 | 1046 |
398 | des-Ile5, His6-All | DRVYPF | 98 | 795.4 | 796 |
399 | des-Asp1-Val3,Ile5,His6-All | RYPF | 99 | 581.3 | 582 |
400 | [Ile4,His3]-des-Asp1,Val3-All | RYHIPF | 98 | 831.4 | 833 |
401 | des-Asp1,Arg2,Val3,Ile5-All | YHPF | 99 | 562.2 | 563 |
402 | des-Asp1,Arg2,Tyr4,His6-All | VIPF | 99 | 474.3 | 475 |
403 | [2-Na1]-des-Asp1-Arg2,Tyr4,His6-All | (2-NaI)-IPF | 97 | 572.3 | 574 |
404 | [2-Na2]-des-Asp1-Arg2,Tyr4,His6-All | V-(2-NaI)-PF | 99 | 558.3 | 559 |
405 | [2-Na3]-des-Asp1-Arg2,Tyr4,His6-All | VI-(2-NaI)-F | 97 | 574.3 | 575 |
406 | [2-Na4]-des-Asp1-Arg2,Tyr4,His6-All | VIP-(2-NaI) | 98 | 523.3 | 524 |
Entry | Sequence | HPLC Purity a | Calculated Mass | Observed Mass b |
---|---|---|---|---|
416 | Glu-Asp-Arg-Orn-Val-Tyr-Ile-His-Pro-Phe | 99% | 1272.4 | 1271.4 |
417 | Glu-Asp-Arg-Lys-Val-Tyr-Ile-His-Pro-Phe | 99% | 1284.4 | 1286.1 |
418 | Asp-Glu-Arg-Val-Orn-Tyr-Ile-His-Pro-Phe | 99% | 1272.4 | 1272.4 |
419 | Asp-Glu-Arg-Val-Lys-Tyr-Ile-His-Pro-Phe | 99% | 1284.4 | 1286.4 |
420 | DGlu-Asp-Arg-Val-Orn-Tyr-Ile-His-Pro-Phe | 98% | 1272.4 | 1272.4 |
421 | Glu-Asp-Arg-Val-DOrn-Tyr-Ile-His-Pro-Phe | 98% | 1272.4 | 1272.4 |
422 | Asp-Arg-Cys-Val-Cys-Tyr-Ile-His-Pro-Phe | 99% | 1249.4 | 1250.4 |
423 | Cys-Asp-Arg-Val-Cys-Tyr-Ile-His-Pro-Phe | 98% | 1249.4 | 1250.4 |
424 | Asp-Cys-Arg-Cys-Val-Tyr-Ile-His-Pro-Phe | 99% | 1249.4 | 1250.4 |
425 | Cys-Asp-Arg-Cys-Val-Tyr-Ile-His-Pro-Phe | 99% | 1249.4 | 1249.4 |
Entry | Sequence | HPLC Purity a (%) | Calculed Mass b (g mol−1) | Observed Mass b (g mol−1) | Antiplasmodial Activity vs. P. gallinaceum (% Fluorescent Sporozoltes) | Antiplasmodial Activity vs. P. falciparum (New Ring Formation%) | Design Rationale |
---|---|---|---|---|---|---|---|
Ang II | DRVYIHPF | 88 | 47 | WT peptide | |||
426 | CDRVYIHPFC | 98 | 1249.6 | 1250 | 92 | 42 | Contrained version of Ang II |
427 | CDRVYHIPFC | 98 | 1249.6 | 1250 | 91 | 42 | Residues H and I were reversed, which is expected to increase antiplasmodial activity based on previously described linear variant. |
428 | CDRVCYHIPF | 98 | 1249.6 | 1250 | 82 | 11 | Designed based on most potent antiplasmodial peptide (CDRVCYIHPF) obtained previously, with an additional 1H reverse modification. |
429 | CDRVYPFC | 97 | 999.4 | 1000 | 95 | 9 | Hydrophobic patch composed of H and I was deleted to asses its influence on functions |
430 | CRYHIPFC | 98 | 1035.5 | 103.6 | 98 | 0 | D and V were deleted to optimize interactions between R and Y within the same plane. I and H were reversed to evaluate the effect of new pi-stack interactions in the activity. |
431 | CRYPFC | 99 | 765.3 | 786 | 4 | 29 | Most important residues for function within the Ang II sequence were kept to build a minimal peptide with antiplasmodial activity. |
432 | CYHPFC | 97 | 766.3 | 767 | 6 | 17 | Only aromatic residues were kept, inspired by the linear form (YHPF), which was one of our lead peptides previously described. |
433 | CVIPFC | 98 | 675.3 | 676 | 7 | 3.5 | Aliphatic and hydrophobic residue F were kept based on previous lead linear peptide (VIPF) |
Peptide | Sequence | H | µH | q | Purity a | Calculated Mass (Da) | Observed Mass b (Da) |
---|---|---|---|---|---|---|---|
Dec-NH2 (434) | SLLSLIRKLIT-NH2 | 0.780 | 0.652 | +3 | 99% | 1254.8 | 1256 |
[Leu]8-Dec-NH2 (435) | SLLSLIRLLIT-NH2 | 1.025 | 0.479 | +2 | 98% | 1239.8 | 1241 |
[Leu]10-Dec-NH2 (436) | SLLSLIRKLLT-NH2 | 0.771 | 0.647 | +3 | 99% | 1254.8 | 1256 |
[Pro]4-Dec-NH2 (437) | SLLPLIRKLIRT-NH2 | 0.849 | 0.583 | +3 | 99% | 1265.8 | 1267 |
[Arg]1-Dec-NH2 (438) | RLLSLIRKLIT- NH2 | 0.692 | 0.704 | +4 | 99% | 1339.9 | 1340 |
[Phe]2-Dec-NH2 (439) | SFLSLIRKLIT- NH2 | 0.788 | 0.659 | +3 | 99% | 1288.8 | 1290 |
[Phe]6-Dec-NH2 (440) | SLLSLFRKLIT- NH2 | 0.779 | 0.651 | +3 | 99% | 1288.8 | 1290 |
[Phe]6-Dec[Thr]11-Dec-NH2 (441) | SLLSLFRKLI- NH2 | 0.831 | 0.392 | +3 | 98% | 1188.8 | 1190 |
Species | Compounds | Sequences | Antiplasmodial Activity (IC50 (µM)) | References |
---|---|---|---|---|
Jatropha ribofilia | Ribifolin (1) | cyclo ILGSIILG | 42 | [3] |
Jatropha curcas | Curcacyline B | cyclo ILGSPILLG | 10,000 | [3,36] |
Jatropha chevalieri | Chevalierin A | cyclo IMGIPILA | 9 | [3,37] |
Jatropha mahafalensis | Mahafacyclin A | cyclo VFGTILG | 16 | [3,38] |
Jatropha mahafalensis | Mahafacyclin B | cyclo FFGTFFG | 2 | [3,39] |
Jatropha pohliana | Pohlianin A | cyclo VLLYPLG | 57 | [3,40] |
Jatropha pohliana | Pohlianin B | cyclo LLLYPLG | 25 | [3,40] |
Jatropha pohliana | Pohlianin C | cyclo FGGTIIFG | 16 | [3,40] |
Compound | P. falciparum KI | MRC-5 |
---|---|---|
2 | 16.4 ± 7 | 51.1 ± 17 |
3 | 17.5 ± 9 | >64.0 |
4 | 12.2 ± 7 | >64.0 |
5 | 27.9 ± 17 | >64.0 |
chloroquine | 0.2 ± 0.1 |
Compound | P. falciparum KI | MRC-5 |
---|---|---|
6 | 3.2 ± 3 | 30.6 ± 4 |
7 | 7.1 ± 2 | >64.0 |
9 | 13.6 ± 9 | >64.0 |
11 | >32.0 | >64.0 |
14 | 7.4 ± 3 | 31.2 ± 1 |
chloroquine | 0.3 ± 0.2 |
Compound | P. falciparum 3D7 | P. falciparum Dd2 | P. falciparum KI |
---|---|---|---|
16 | 1.5 | 1.6 | 1.3 |
17 | 1.5 | 1.1 | 0.83 |
chloroquine | 0.041 | 0.52 | 0.46 |
Compound | Blood-Stage P. falciparum | Liver-Stage P. berghei | HEK2931 Cytotoxicity | HepG2 Cytotoxicity |
---|---|---|---|---|
18 | 8.9 | 11, >12 | >23 | >23 |
Atovaquone (+control) | 0.0061 | <0.00028, 0.0017, 0.0037 | >2.0 | not tested |
Compound | IC50 (μM) | ||||
---|---|---|---|---|---|
Antiplasmodial Activity | Cytotoxicity | Selectivity Index | |||
pf KI a | pf FCR3 b | MRC-5 | MRC-5/pf KI | MRC-5/pf FCR3 | |
20 | 12.5 ± 1 | 17.1 ± 1.0 | 6.8 ± 2 | 0.5 | 0.4 |
21 | 0.83 ± 0.04 | 0.89 ± 0.04 | 14.7 ± 4 | 18.4 | 16.3 |
artemisinin c | 0.022 ± 0.001 | 0.026 ± 0.003 | >25 | >1136 | >961 |
Compound | Inhibition (%) |
---|---|
20 | 18.3 ± 6 |
21 | 41.0 ± 2 |
Artesunate a | 99.7 ± 0.10 |
Compound | NF54 | Dd2 | 3D7 |
---|---|---|---|
23 | 3.93 | 3.30 | 8.65 |
24 | 2.61 | 1.72 | 2.10 |
25 | >10 | 4.37 | >10 |
26 | 3.73 | 1.07 | 2.52 |
27 | 3.05 | 2.02 | >10 |
28 | >10 | >10 | >10 |
29 | >10 | >10 | >10 |
CQ | 0.03 | 1.28 | >10 |
Entry | Compound | R′ | R″ | R‴ | Pfalcp IC50 [nm] 3D7 | IC50 [nm] Dd2 | Mtb MIC [µM] wt | Overall Synthetic Steps |
---|---|---|---|---|---|---|---|---|
ref Mtb | Isoniazid | 0.9 | ||||||
ref Pfalcp | CQ | 3.4 | 233.9 | |||||
1 | desoxycyclomarin C | Me | 39.8 | NA | 0.9 | 37 | ||
2 | 96 | Me | 9.0 | 12.9 | 0.5 | 34 | ||
3 | 97 | Me | 4.4 | 6.5 | 1.7 | 31 | ||
4 | 98 | iPr | Me | 47.8 | 76.0 | 0.4 | 36 | |
5 | 99 | Me | Me | 13.4 | 17.8 | 0.9 | 31 | |
6 | 100 | H | Me | 28.1 | 27.5 | 1.5 | 31 | |
7 | 106 | Me | 34.4 | 71.8 | 21.2 | 32 | ||
8 | 107 | Me | 57.6 | 200.2 | 1.7 | 33 | ||
9 | 108 | iPr | Me | 355.7 | 300.3 | 0.4 | 34 | |
10 | 109 | Me | Me | 230.3 | 256.7 | 1.6 | 29 | |
11 | 110 | H | Me | 314.2 | 421.5 | 0.5 | 29 | |
12 | 119 | H | 47.9 | 36.7 | 2.3 | 32 | ||
13 | 120 | H | 452.0 | 346.5 | >32 | 33 | ||
14 | 121 | iPr | H | 177.5 | 287.8 | 1.8 | 34 | |
15 | 122 | Me | H | 362.4 | 318.4 | 3.4 | 32 | |
16 | 123 | H | 303.5 | 260.8 | 2.6 | 30 | ||
17 | 124 | H | 428.5 | 305.1 | 3.2 | 31 | ||
18 | 125 | H | H | 287.4 | 196.7 | 4.3 | 36 |
Compound | EC50 P. falciparum K1 (µM) | Compound | EC50 P. falciparum K1 (µM) |
---|---|---|---|
140 | 0.028 ± 0.006 | 148 | 4.6 ± 1 |
141 | 0.68 ± 0.04 | 149 | 8.4 ± 1 |
142 | 6.50 ± 0.05 | 150 | 0.73 ± 0.06 |
143 | 16.8 ± 1 | 151 | 0.47 ± 0.04 |
144 | 43.1 ± 1 | 152 | 0.42 ± 0.05 |
145 | 0.42 ± 0.03 | 153 | >50 |
146 | >10 | 154 | >50 |
147 | 3.8 ± 1 |
Cyclopeptide | EC50/EC50 P. falciparum K1 (µM) b | EC50 P. falciparum 3D7 (µM) c | SI IC50 d/IC50 PfK1 | SI IC50 e/IC50 Pf3D7 |
---|---|---|---|---|
156 | 8.0 ± 0.5/39 ± 3 | 3.8 ± 0.1 | >1250 | >6.6 × 104 |
157 | 0.008 ± 0.004/1.0 ± 0.5 | 0.25 ± 0.02 | >1.3 × 107 | >1.0 × 106 |
158 | 0.040 ± 0.006/1.0 ± 0.3 | 1.0 ± 0.3 | >2.5 × 106 | >2.5 × 105 |
159 | 0.13 ± 0.04/4.0 ± 0.6 | 1.4 ± 0.6 | >7.7 × 105 | >1.8 × 105 |
160 | 9.0 ± 0.5/59 ± 3 | 1.8 ± 0.1 | >1.1 × 104 | > 1.4 × 105 |
161 | 150 ± 5/900 ± 9 | nt | nt | nt |
163 | nt | 5400 ± 100 | nt | >46 |
164 | nt | 210 ± 10 | nt | >1.2 × 103 |
165 | 0.20 ± 0.04/4.0 ± 0.6 | 12 ± 1 | 5 × 105 | >2 × 104 |
Bioactivity/ADME Profile Compound 177 | Values |
---|---|
antimicrobial activities | |
MIC (Mtb H73Rv) | >80 µM |
MIC (M. vaccae) | 18.8 µM |
IC50 (P. falciparum 3D7) | 2.3 µM |
cytotoxicity | |
IC50 (Hep2G cells) | >100 µM |
membrane permeability a | 280 nm/s |
% human serum albumin binding | 88% |
Intrinsic microsomal clearance (Clint) | |
Human | 46.53 mL/(min g) tissue |
Mouse | 38.3 mL/(min g) tissue |
Plasma stability (% remain after 2 h incubation) b | |
Human plasma | 103% |
Mouse plasma | 18% |
EC50 (µM) | β5 IC50 (µM) | Permeability | Liver Microsomal Stability | Kinetic Solubility | Cytotoxicity HepG2 | Lipopholicity | ||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
ID | R1 | R2 | 3D7 | Pf20S | c20S | i20S | PAMPA | MDR | m/hLM | pH 6.8 | Viability % | cLogP |
cyclic peptide 201 | A | 0.078 | 0.13 | >100 | >100 | Un-detected | >2.9/<1 | 90.6 179.4 | <1.6 | 71 | 6.3 | |
202 | A | 0.002 | 0.017 | >100 | >100 | 22 | >34/1 | 171.3 N.D. | - | 93 | 6.2 | |
203 | B | 0.003 | 0.014 | 4.0 | >100 | 151 | >0.71/<4 | 269.7 11.2 | <1.4 | 93 | 4.7 | |
204 | B | 0.0002 | 0.003 | 26.3 | >100 | 214 | 31/5 | >768 644.3 | 3.8 | 77 | 5.3 | |
214 | - | - | 0.002 | 0.019 | 2.4 | >100 | 187 | 53/2 | 566.6 349.8 | 76 | 97 | 4.2 |
220 | - | - | 0.019 | 0.080 | 6.4 | >100 | 120 | 89/2 | 397.4 275.7 | >130 | 109 | 3.0 |
EC50 (µM) | β5 IC50 (µM) | Permeability | Metabolic Stability | Kinetic Solubility | Cytotoxicity HepG2 | Lipopholicity | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
ID | P1 | 3D7 | Pf20S | c20S | i20S | PAMPA | MDR | m/hLM | pH 6.8 | Viability % | cLogP |
220 | 0.002 | 0.019 | 2.4 | >100 | 187 | 53/2 | 566.6 349.8 | 76 | 97 | 4.2 | |
221 | 0.008 | 0.022 | 8.9 | >100 | 72 | >11/<5 | 288 187.7 | 35 | 101 | 4.0 | |
222 | 0.003 | 0.007 | 3.0 | >100 | 103 | 68/2 | 477.6 340.6 | 49 | 101 | 4.4 | |
223 | 0.008 | 0.054 | 9.8 | >100 | 11 | >6/<1 | 261 187.7 | >120 | 107 | 3.4 | |
224 | >2.77 | 23.8 | >100 | >100 | - | - | - | - | - | 4.8 | |
225 | >2.77 | 9.0 | >100 | >100 | 160 | 11/17 | >768 672.1 | 6.2 | 109 | 3.3 | |
226 | >2.77 | 64.0 | >100 | >100 | 82 | >21/<1 | 59.6 28.6 | 2 | 103 | 3.7 | |
227 | 0.398 | 2.5 | >100 | >100 | 145 | 44/2 | 703.4 288 | 31 | 111 | 4.5 | |
228 | 0.001 | 0.003 | 2.5 | >100 | 151 | 57/3 | 657.8 596.5 | 100 | 96 | 4.9 |
EC50 (µM) | β5 IC50 (µM) | Permeability | Metabolic Stability | Kinetic Solubility | Cytotoxicity HepG2 | Lipopholicity | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
ID | P3 | 3D7 | Pf20S | c20S | i20S | PAMPA | MDR | m/hLM | pH 6.8 | Viability % | cLogP |
228 | 0.001 | 0.003 | 2.5 | >100 | 151 | 57/3 | 657.8 596.5 | 100 | 96 | 4.9 | |
247 | 0.072 | 0.91 | 13.1 | >100 | 208 | 529 405 | 20 | 104 | 4.5 | ||
254 | 0.011 | 0.009 | 2.7 | 51.0 | 212 | 45/3 | >768 618 | 17 | 100 | 5.0 | |
272 | 0.012 | 0.043 | 3.2 | 46.5 | 133 | 49/1 | 128 113 | >130 | 102 | 2.8 | |
TDI8304 | 0.016 | 0.081 | >100 | >100 | 15 | >2/<1 | 6 19 | >130 | 103 | 2.4 |
EC50 (µM) | β5 IC50 (µM) | Permeability | Metabo-lic Stability | Kinetic Solubility | Cytotoxicity HepG2 | Lipopholicity | TPSA | |||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
ID | P3 | 3D7 | Pf20S | c20S | i20S | PAMPA | MDR | m/hLM | pH 6.8 | Viability % | cLogP | |
TDI8304 | - | 0.016 | 0.081 | >100 | >100 | 15 | >2/<1 | 6 19 | >130 | 103 | 2.4 | 129.3 |
249 | Gemdime-thyl | 0.096 | 0.21 | 45.2 | >100 | 269 | 35/11 | 690 167 | 90 | 97 | 3.7 | 109 |
271 | 0.034 | 0.56 | 31.1 | >100 | 89 | >28/<1 | 5 4 | 68 | 102 | 2.4 | 118 | |
273 | 0.32 | 4.9 | >100 | >100 | 0 | >2/<1 | −14 −26 | >140 | 100 | 2.2 | 121 | |
248 | 0.7 | 3.9 | >100 | >100 | 20 | 1.2/5 | −1 15 | >130 | 104 | 2.8 | 99.8 | |
270 | 0.32 | 2.0 | 13.1 | 17.6 | 0 | >2/<1 | −27 6 | >140 | 100 | 2.9 | 112.2 |
Compound | IC50 (µM) |
---|---|
296 | 1.6 |
297 | 1.2 |
298 | 1.4 |
299 | >10 |
300 | 1.3 |
301 | 3.3 |
302 | 0.14 |
303 | 2.4 |
Analogue | IC50 FP-2 [nM] | IC50 FP-3 [nM] | IC50 P. falciparum (3D7) [nM] |
---|---|---|---|
309 | 6.78 ± 0.44 | 292 ± 1 | 8.93 ± 73 |
310 | 2.81 ± 0.39 | 163 ± 21 | 210 ± 80 |
311 | 3710 ± 420 | >50,000 | 4375 ± 690 |
312 | >50,000 | >50,000 | >50,000 |
Analogue | IC50 FP-2 [nM] | IC50 FP-3 [nM] | IC50 P. falciparum (3D7) [nM] |
---|---|---|---|
313 | 10,500 ± 640 | >25,000 | 540 ± 210 |
314 | 7700 ± 190 | >50,000 | 1900 ± 620 |
315 | 11,500 ± 190 | >25,000 | 320 ± 10 |
316 | 2500 ± 150 | 34,000 ± 460 | 1100 ± 800 |
317 | 3400 ± 390 | >25,000 | 5400 ± 380 |
318 | 6000 ± 160 | 46,000 ± 5400 | 6600 ± 3800 |
Analogue | IC50 FP-2 [nM] | IC50 FP-3 [nM] | IC50 P. falciparum (3D7) [nM] |
---|---|---|---|
309 | 6.78 ± 0.44 | 292 ± 1 | 89.3 ± 73 |
346 | 24.8 ± 23 | 225 ± 27 | 57.3 ± 26 |
347 | 9.52 ± 0.14 | 131 ± 44 | 16.6 ± 9 |
348 | 5.25 ± 2 | 81.4 ± 8 | 20.0 ± 8 |
349 | 12.0 ± 3 | 66.7 ± 25 | 9.7 ± 2 |
350 | 9.59 ± 0.21 | 196 ± 7 | 96.0 ± 74 |
351 | 6.86 ± 3 | 182 ± 16 | 62.0 ± 47 |
CQ | 17.3 ± 3 |
Analog | IC50 P. falciparum (Dd2) [nM] | HEK298 [nM] | AP M1, M17, and M18 [nM] |
---|---|---|---|
309 | 302 ± 126 | 14 200 ± 1050 | >10,000 |
313 | 421 ± 2 | >50,000 | >10,000 |
315 | 378 ± 20 | >50,000 | >10,000 |
317 | 170 ± 68 | >50,000 | >10,000 |
346 | 419 ± 185 | 16,300 ± 1700 | >10,000 |
347 | 165 ± 68 | 9650 ± 1480 | >10,000 |
348 | 67.0 ± 30 | 18,900 ± 110 | >10,000 |
349 | 29.0 ± 16 | 8500 ± 124 | >10,000 |
Compound | IC50 FP-2 [nM] | IC50 FP-3 [nM] | IC50 3D7 [nM] | IC50 W2 [nM] |
---|---|---|---|---|
352 | 12 | 67 | 9.7 | ND |
371 | 59 | 131 | 14 | 11 |
372 | 31 | 117 | 26 | 28 |
373 | 29 | 79 | 42 | 49 |
374 | 60 | 851 | 24 | 10 |
375 | 57 | 228 | 5 | 7 |
376 | 3097 | 10,235 | 2593 | 691 |
377 | 3523 | 8788 | 1248 | 478 |
378 | 464 | 459 | 229 | 119 |
379 | 235 | 407 | 72 | 37 |
380 | 455 | 547 | 164 | 55 |
381 | 156 | 480 | 205 | 59 |
382 | >50,000 | >50,000 | >10,000 | 3729 |
383 | >50,000 | >50,000 | 6994 | 1017 |
384 | 84 | 484 | 9 | 10 |
385 | 169 | 490 | 83 | 95 |
386 | 270 | 2571 | 76 | 54 |
387 | 33 | 112 | 1 | 4 |
CQ | ND | ND | 4 | 55 |
ART | ND | ND | 32 | 21 |
E64 | 68 | 136 | ND | ND |
Degradation Half-Life (min) | ||||||
---|---|---|---|---|---|---|
352 | 372 | 373 | 375 | 384 | 387 | |
plasma | <2 | 126 | 82 | 557 | >600 | 373 |
blood | <2 | 41 | 17 | 110 | >600 | 273 |
Peptides | Act > 50% | Shared Volume % |
---|---|---|
SE5 P1 (388) | 1 | 50.1 |
SE5 P2 (389) | 1 | 57.5 |
SE5 P3 (390) | 0 | 27.9 |
SE5 P4 (391) | 0 | 41.6 |
SE5 P5 (392) | 0 | 19.9 |
SE5 P6 (393) | 0 | 43.5 |
SE5 P7 (394) | 0 | 45.1 |
SE5 P8 (395) | 0 | 40.2 |
SE5 P9 (396) | 0 | 39.2 |
MHC [M] | MIC [M] | MHC/MIC | |
---|---|---|---|
Ang II | 10−5 | 10−12 | 107 |
Peptide 401 | 10−5 | 10−14 | 109 |
Peptide 402 | 10−6 | 10−14 | 108 |
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Kurniaty, N.; Maharani, R.; Hidayat, A.T.; Supratman, U. An Overview on Antimalarial Peptides: Natural Sources, Synthetic Methodology and Biological Properties. Molecules 2023, 28, 7778. https://doi.org/10.3390/molecules28237778
Kurniaty N, Maharani R, Hidayat AT, Supratman U. An Overview on Antimalarial Peptides: Natural Sources, Synthetic Methodology and Biological Properties. Molecules. 2023; 28(23):7778. https://doi.org/10.3390/molecules28237778
Chicago/Turabian StyleKurniaty, Nety, Rani Maharani, Ace Tatang Hidayat, and Unang Supratman. 2023. "An Overview on Antimalarial Peptides: Natural Sources, Synthetic Methodology and Biological Properties" Molecules 28, no. 23: 7778. https://doi.org/10.3390/molecules28237778
APA StyleKurniaty, N., Maharani, R., Hidayat, A. T., & Supratman, U. (2023). An Overview on Antimalarial Peptides: Natural Sources, Synthetic Methodology and Biological Properties. Molecules, 28(23), 7778. https://doi.org/10.3390/molecules28237778