Diketoacid chelating ligands as dual inhibitors of HIV-1 integration process.
HIV-1 Integrase (IN) represents a very attractive pharmacological target for the development of new and more efficient drugs. Recently, an allosteric inhibitory approach also emerged, that targets the interaction between IN and cellular cofactors, such as LEDGF/p75. Small molecules based on the diketoacid pharmachophore were studied for their ability to inhibit at the same time integration and IN-LEDGF/p75 interaction (dual inhibitors): in this study, we evaluated three indole diketoacid derivatives and their magnesium(II) complexes for their ability to act as dual inhibitors. Effectively, the metal complexes exhibited IN inhibition potency in low nanomolar/micromolar concentration range; both the complexes and the free ligands are also able to inhibit the IN-LEDGF/p75 interaction at low μM values. Moreover, these magnesium compounds showed good antiviral activity, suggesting the possibility to exploit metal coordination for the design of new antivirals.
Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, I-43124 Parma, Italy. Electronic address: dominga.rogolino@unipr.it.
Dominga
D
Rogolino
Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, I-43124 Parma, Italy.
Mauro
M
Carcelli
Dipartimento di Farmacia, Università di Parma, Parco Area delle Scienze 23/A, I-43124 Parma, Italy.
Carlotta
C
Compari
Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
Laura
L
De Luca
Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy.
Stefania
S
Ferro
Dipartimento di Farmacia, Università di Parma, Parco Area delle Scienze 23/A, I-43124 Parma, Italy.
Emilia
E
Fisicaro
Dipartimento di Chimica, Università di Parma, Parco Area delle Scienze 17/A, I-43124 Parma, Italy.
Gabriele
G
Rispoli
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, North Campus Research Complex, 2800 Plymouth Road, Ann Arbor, MI 48109-2800, USA.
Nouri
N
Neamati
Laboratory for Molecular virology and Gene Therapy, Division of Molecular Medicine, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
Zeger
Z
Debyser
Laboratory for Molecular virology and Gene Therapy, Division of Molecular Medicine, KU Leuven, Kapucijnenvoer 33, 3000 Leuven, Belgium.
Frauke
F
Christ
Dipartimento di Scienze del Farmaco e Prodotti per la Salute, Università di Messina, Viale Annunziata, I-98168 Messina, Italy. Electronic address: achimirri@unime.it.
Alba
A
Chimirri
D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D007651:Keto Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D016662:Virus Integration / Q000187:drug effects*
D019380:Anti-HIV Agents; D002614:Chelating Agents; D019428:HIV Integrase Inhibitors; D007651:Keto Acids; D019427:HIV Integrase
Antiviral agents; Diketo acid; Dual inhibitors; HIV-1 integrase inhibitors; LEDGF/p75 protein–protein inhibitors; Magnesium complexes