An elite scaffold and a wonder pharmacophore in drug discovery: Styrylquinoline

: Styrylquinoline is quinoline molecule linked to phenyl rings with an unsaturated ethylene linker, resulting in a flat and rigid conformation. The synthesis of the molecule was reported almost a century ago but was not much explored due to its adverse toxicity and poor selectivity. In the last two decades plethora of work was reported related to synthesis and antiretroviral activity of several styrylquinoline derivatives. Later, other activities such as their antimicrobial and anticancer abilities of these derivatives were also reported. In this review, we summarize the diverse steps of the development and analyze the spectrum of the activity of styrylquinolines and their utilization in drug design. Styrylquinolines are extensively explored for new pharmacological activities in recent years and this makes the moiety to gain more visibility as a potential drug candidate and lead molecule in medicinal chemistry. The data obtained in vitro and ex vivo shed light on their different mechanism of actions. Styrylquinolines have proved to be potential lead molecule in medicinal chemist’s tool kit due to exploration of variety of avenues of its activity as a drug candidate.

Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification

SAMHD1 impedes infection of myeloid cells and resting T lymphocytes by retroviruses, and the enzymatic activity of the protein—dephosphorylation of deoxynucleotide triphosphates (dNTPs)—implicates enzymatic dNTP depletion in innate antiviral immunity. Here we show that the allosteric binding sites of the enzyme are plastic and can accommodate oligonucleotides in place of the allosteric activators, GTP and dNTP. SAMHD1 displays a preference for oligonucleotides containing phosphorothioate bonds in the Rp configuration located 3’ to G nucleotides (GpsN), the modification pattern that occurs in a mechanism of antiviral defense in prokaryotes. In the presence of GTP and dNTPs, binding of GpsN-containing oligonucleotides promotes formation of a distinct tetramer with mixed occupancy of the allosteric sites. Mutations that impair formation of the mixed-occupancy complex abolish the antiretroviral activity of SAMHD1, but not its ability to deplete dNTPs. The findings link nucleic acid binding to the antiretroviral activity of SAMHD1, shed light on the immunomodulatory effects of synthetic phosphorothioated oligonucleotides and raise questions about the role of nucleic acid phosphorothioation in human innate immunity.

Natural cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling

GPR15 is a G protein-coupled receptor (GPCR) proposed to play a role in mucosal immunity that also serves as a major entry cofactor for HIV-2 and simian immunodeficiency virus (SIV). To discover novel endogenous GPR15 ligands, we screened a hemofiltrate (HF)-derived peptide library for inhibitors of GPR15-mediated SIV infection. Our approach identified a C-terminal fragment of cystatin C (CysC95-146) that specifically inhibits GPR15-dependent HIV-1, HIV-2, and SIV infection. In contrast, GPR15L, the chemokine ligand of GPR15, failed to inhibit virus infection. We found that cystatin C fragments preventing GPR15-mediated viral entry do not interfere with GPR15L signaling and are generated by proteases activated at sites of inflammation. The antiretroviral activity of CysC95-146 was confirmed in primary CD4+ T cells and is conserved in simian hosts of SIV infection. Thus, we identified a potent endogenous inhibitor of GPR15-mediated HIV and SIV infection that does not interfere with the physiological function of this GPCR.

Natural Cystatin C fragments inhibit GPR15-mediated HIV and SIV infection without interfering with GPR15L signaling

SUMMARYGPR15 is a G protein-coupled receptor proposed to play a role in mucosal immunity that also serves as entry cofactor for HIV and SIV. To discover novel endogenous GPR15 ligands, we screened a hemofiltrate-derived peptide library for inhibitors of GPR15-mediated SIV infection. Our approach identified a C-terminal fragment of Cystatin C (CysC95-146) that specifically inhibits GPR15-dependent HIV-1, HIV-2 and SIV infection. In contrast, GPR15L, the chemokine ligand of GPR15, failed to inhibit virus infection. We found that Cystatin C fragments preventing GPR15-mediated viral entry do not interfere with GPR15L signaling and are generated by proteases activated at sites of inflammation. The antiretroviral activity of CysC95-146 was confirmed in primary CD4+ T cells and is conserved in simian hosts of SIV infection. Thus, we identified a potent endogenous inhibitor of GPR15-mediated HIV and SIV infection that does not interfere with the physiological function of this G protein-coupled receptor.

Styrylquinoline – A Versatile Scaffold in Medicinal Chemistry

Background: : Styrylquinolines are characteristic fully aromatic compounds with flat, rather lipophilic structures. The first reports on their synthesis and biological activity were published roughly a century ago. However, their low selectivity, unfavorable toxicity and problems with their mechanism of action significantly hampered their development. As a result, they have been abandoned for most of the time since they were discovered. Objective: : Their renaissance was observed by the antiretroviral activity of several styrylquinoline derivatives that have been reported to be HIV integrase inhibitors. Subsequently, other activities such as their antifungal and anticancer abilities have also been revisited. Methods: In the present review, the spectrum of the activity of styrylquinolines and their use in drug design is presented and analyzed. Results: New properties and applications that were reported recently have re-established styrylquinolines within medicinal and material chemistry. The considerable increase in the number of published papers regarding their activity spectrum will ensure further discoveries in the field. Conclusions: Styrylquinolines have earned a much stronger position in medicinal chemistry due to the discovery of their new activities, profound mechanisms of action and as drug candidates in clinical trials.

Antibacterial Activity of Cuttlefish Sepia sp. (Cephalopoda,) Ink Extract Against Aeromonas hydrophila

Cephalopods ink has shown potential antiretroviral activity. The ink extracts of cuttlefish showed an antibacterial effect. This study aims to investigate the antibacterial activity of the methanolic extract of the ink of cuttlefish Sepia sp. against Aeromonas hydrophila. A. hydrophila are opportunists and associated with aquatic fish and shrimp disease. The shade-dried ink sample from approximately 30g ink sacs obtained from 15 animals was immersed separately in methanol (1:3 w/v) solvents for overnight. The experiment in this study used the dried extract of cuttlefish ink. The isolate of A. hydrophila was originated from Jepara Brackishwater Aquaculture Center. The average yield percentage of cuttlefish ink extract obtained was 4.86%. The results of the MIC test in Table V show that the highest average absorbance value obtained was at a concentration of 50 ppm, which was equal to 1.716 nm, and the lowest absorbance was obtained at a treatment dose of 300 ppm at 0.841 nm, while the Mc Farland tube was 0.933 nm. The results of antibacterial test on Table II showed antibacterial activity of cuttlefish ink extract at negative concentration control showed diameter zone of 5 ± 1.2 mm, at positive control showed diameter zone of 31 ± 1.2 mm, at 250 ppm result 19 ± 0.9 mm, at 300 ppm result 22 ± 1.4 mm, at 350 ppm result 31 ± 1.2 mm.

Ibalizumab, a Novel Monoclonal Antibody for the Management of Multidrug-Resistant HIV-1 Infection

ABSTRACT Limited antiretrovirals are currently available for the management of multidrug-resistant (MDR) HIV-1 infection. Ibalizumab, a recombinant humanized monoclonal antibody, represents the first novel agent for HIV-1 management in over a decade and is the first monoclonal antibody for the treatment of MDR HIV-1 infection in combination with other forms of antiretroviral therapy in heavily treatment-experienced adults who are failing their current antiretroviral regimen. Ibalizumab demonstrates a novel mechanism of action as a CD4-directed postattachment inhibitor and has a favorable pharmacokinetic profile that allows for a dosing interval of every 14 days after an initial loading dose. Clinical studies have demonstrated reasonably substantial antiretroviral activity with ibalizumab among a complex patient population with advanced HIV-1 infection who are receiving an optimized background regimen, where limited therapeutic options exist. Ibalizumab was well tolerated in clinical trials, and the most common adverse effects included diarrhea, nausea, dizziness, fatigue, pyrexia, and rash. Resistance to ibalizumab has also been observed via reduced expression or loss of the potential N-linked glycosylation sites in the V5 loop of the envelope glycoprotein 120. The mechanism of action, pharmacokinetic parameters, efficacy, and safety of ibalizumab present an advance in the management of MDR HIV-1 infection. Future studies and postmarketing experience will further determine longer-term clinical efficacy, safety, and resistance data for ibalizumab.