Development of peptide/guanidine bioconjugates with anti-Leishmania activity

• Grant number: 22/05411-8
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2022
• End date: November 30, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Eduardo Maffud Cilli
• Grantee: Eduardo Maffud Cilli
• Host Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• City of the host institution: Araraquara
• Associated researchers: Eduardo Rene Perez Gonzalez ; Marcia Aparecida Silva Graminha

Abstract

Leishmaniasis correspond to a group of diseases caused by protozoa of the genus Leishmania. According to the Pan American Health Organization (PAHO), in the last 20 years, 1,067,759 cases of cutaneous (CL) and mucosal (LM) leishmaniasis were reported. Parasitic diseases represent a major public health problem, especially considering the growing number of immunocompromised patients and those living in poverty. However, there are few therapeutic options available for the treatment of these diseases, and the existing ones are ineffective and have side effects. Thus, the search for new therapeutic alternatives is very important. The main goal of this work is the production of peptide/guanidine bioconjugates to increase the potency of these molecules. In this project, antimicrobial and cellular penetration peptides will be coupled to antileishmanial guanidines, aiming to increase both selectivity and potency of these molecules. The temporine antimicrobial peptide (TSHa), which has leishmanicidal activity, will be coupled to at least three guanidinic anti-Leishmania compounds, called GVLs. One of the guanidines will also be coupled to the cellular penetration peptides AIP-6, PFV and HIV-TAT, previously described as good carriers through cell membranes, aiming to increase guanidine permeation and consequently their intracellular concentration and activity. The peptide desCys11/Lys12/Lys13(p-BthTX-I)2K and the dimeric derivative of TSHa ((TSHa)2K) will also be evaluated. Preliminary data showed that the TSHa bioconjugate linked to a guanidine has more potent anti-amastigote and anti-promastigote activity than the original molecules and showed greater selectivity for parasites than to the host cells. Thus, this project aims to develop new drugs for the treatment of leishmaniasis. (AU)

Scientific publications

(11)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

COELHO, NATALIA C. S.; PORTUONDO, DEIVYS L. F.; LIMA, JHONATAN; VELASQUEZ, ANGELA M. A.; VALENTE, VALERIA; CARLOS, IRACILDA Z.; CILLI, EDUARDO M.; GRAMINHA, MARCIA A. S.. Peptide Dimerization as a Strategy for the Development of Antileishmanial Compounds. Molecules, v. 29, n. 21, p. 21-pg., 2024-11-01. (20/04415-4, 22/05411-8, 13/07600-3)

COSTA, NATALIA C. S.; DOS ANJOS, LUANA RIBEIRO; DE SOUZA, JOAO VICTOR MARCELINO; BRASIL, MARIA CAROLINA OLIVEIRA DE ARRUDA; MOREIRA, VITOR PARTITE; GRAMINHA, MARCIA A. S.; LUBEC, GERT; GONZALEZ, EDUARDO RENE P.; CILLI, EDUARDO MAFFUD. Development of New Leishmanicidal Compounds via Bioconjugation of Antimicrobial Peptides and Antileishmanial Guanidines. ACS OMEGA, v. 8, n. 37, p. 9-pg., 2023-09-06. (21/02595-8, 22/05411-8)

DE SOUZA, JOAO VICTOR MARCELINO; COSTA, NATALIA C. S.; BRASIL, MARIA C. O. ARRUDA; DOS ANJOS, LUANA RIBEIRO; DE MENEZES, RENATA PRISCILA BARROS; ZAMPIERI, EDUARDO HENRIQUE; DE LIMA, JHONATAN SANTOS; VELASQUEZ, ANGELA MARIA ARENAS; SCOTTI, LUCIANA; SCOTTI, MARCUS TULLIUS; et al. Guanidines Conjugated with Cell-Penetrating Peptides: A New Approach for the Development of Antileishmanial Molecules. Molecules, v. 30, n. 2, p. 17-pg., 2025-01-01. (21/02595-8, 20/04415-4, 13/07600-3, 22/05411-8)

BICHO, GABRIEL F. H.; NUNES, LETICIA O. C.; FIAMETTI, LOUISE OLIVEIRA; ARGENTIN, MARCELA N.; CANDIDO, VITORIA T.; CAMARGO, ILANA L. B. C.; CILLI, EDUARDO M.; SANTOS-FILHO, NORIVAL A.. Synthesis, Characterization, and Study of the Antimicrobial Potential of Dimeric Peptides Derived from the C-Terminal Region of Lys⁴⁹ Phospholipase A₂ Homologs. TOXINS, v. 16, n. 7, p. 14-pg., 2024-07-01. (23/03857-1, 22/05411-8, 13/07600-3)

SANCHES, PAULO RICARDO DA S.; FARIA, JOAO CALDANA ELIAS DE CAMPOS; BITTAR, CINTIA; OLIVIERI, HUGO ALEXANDRE SIQUEIRA GUBEROVICH; MESQUITA, NATHALYA CRISTINA DE MORAES ROSO; NOSKE, GABRIELA DIAS; DE GODOY, ANDRE SCHUTZER; OLIVA, GLAUCIUS; RAHAL, PAULA; CILLI, EDUARDO MAFFUD. The GA-Hecate Peptide inhibits the ZIKV Replicative Cycle in Different Steps and can Inhibit the Flavivirus NS2B-NS3 Protease after Cell Infection. PROTEIN AND PEPTIDE LETTERS, v. 31, n. 7, p. 12-pg., 2024-07-19. (22/11644-5, 20/05761-3, 22/05411-8, 19/08342-4, 13/07600-3, 20/12519-4, 15/23244-8)

AYUSSO, GABRIELA MIRANDA; SANCHES, PAULO RICARDO DA SILVA; CARVALHO, TAMARA; SANTOS, IGOR ANDRADE; MARTINS, DANIEL OLIVEIRA SILVA; LIMA, MARIA LETICIA DUARTE; DA CONCEICAO, PAMELA JOYCE PREVIDELLI; BITTAR, CINTIA; MERITS, ANDRES; CILLI, EDUARDO MAFFUD; et al. The Synthetic Peptide GA-Hecate and Its Analogs Inhibit Multiple Steps of the Chikungunya Virus Infection Cycle In Vitro. PHARMACEUTICALS, v. 16, n. 10, p. 17-pg., 2023-10-01. (19/07784-3, 22/05411-8, 19/10150-6)

SANCHES, PAULO RICARDO DA SILVA; SANCHEZ-VELAZQUEZ, RICARDO; BATISTA, MARIANA NOGUEIRA; CARNEIRO, BRUNO MOREIRA; BITTAR, CINTIA; DE LORENZO, GIUDITTA; RAHAL, PAULA; PATEL, ARVIND H.; CILLI, EDUARDO MAFFUD. Antiviral Evaluation of New Synthetic Bioconjugates Based on GA-Hecate: A New Class of Antivirals Targeting Different Steps of Zika Virus Replication. Molecules, v. 28, n. 13, p. 20-pg., 2023-07-01. (13/07600-3, 22/05411-8, 15/23244-8, 20/05761-3, 20/12519-4, 19/08342-4)

METZ, GERMAN ERNESTO; AZCURRA, MIRIAM BEATRIZ; DE SOUZA, GUILHERME SASTRE; BRASIL, MARIA CAROLINA OLIVEIRA DE ARRUDA; CILLI, EDUARDO MAFFUD; LORENZON, ESTEBAN NICOLAS. Inactivation of Equine Arteritis Virus by Indolicidin Peptide. INTERNATIONAL JOURNAL OF PEPTIDE RESEARCH AND THERAPEUTICS, v. 31, n. 3, p. 5-pg., 2025-02-17. (22/05411-8)

LIMA, MARIA LETICIA DUARTE; SANCHES, PAULO RICARDO DA SILVA; GERALDINI, DAYLA BOTT; AYUSSO, GABRIELA MIRANDA; DA CONCEICAO, PAMELA JOYCE PREVIDELLI; CARVALHO, TAMARA; GONZALEZ, JORGE ENRIQUE HERNANDEZ; GISMENE, CAROLINA; BITTAR, CINTIA; ARNI, RAGHUVIR KRISHNASWAMY; et al. A new synthetic peptide GA-KKALKKLKKALKKAL-CONH2 exhibits antiviral activity against ZIKV in multiple stages of the replicative cycle. VIROLOGY, v. 611, p. 12-pg., 2025-07-29. (22/03901-8, 23/02956-6, 23/04491-0, 24/00876-8, 19/07784-3, 24/13327-2, 20/05761-3, 22/05411-8, 20/08615-8)

DA SILVA SANCHES, PAULO RICARDO; CILLI, EDUARDO MAFFUD. The Use of Virus-like Particles as Immunogens to Treat Infectious Diseases. CURRENT TOPICS IN MEDICINAL CHEMISTRY, v. N/A, p. 11-pg., 2025-07-17. (23/02956-6, 20/05761-3, 22/05411-8)

MARINHO RIGHETTO, GABRIELA; SANTOS-FILHO, NORIVAL ALVES; CATARIN NUNES, LETICIA OLIVEIRA; ANDRE, CAMILLE; SOUZA, JULIA MEDEIROS; ANDRICOPULO, ADRIANO DEFINI; MARTINS BISPO, PAULO JOSE; CILLI, EDUARDO MAFFUD; BARATELLA DA CUNHA CAMARGO, ILANA LOPES. Optimizing Bothropstoxin-I-Derived Peptides: Exploring the Antibacterial Potential of p-BthW. ACS OMEGA, v. 9, n. 22, p. 13-pg., 2024-05-22. (22/05411-8, 13/07600-3, 18/15887-4)