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Vikas Yadav

Publications and source records attributed to Vikas Yadav.

11 recordsLinked to original sources
PubMed2026

Mycodnaviridae is a clade of giant viruses that persistently infect zoosporic fungi.

Giant viruses of the phylum Nucleocytoviricota have emerged as particularly notable due to their increasingly recognized impacts on eukaryotic genome evolution. Their origins are hypothesized to predate or coincide with the diversification of eukaryotes, and they have been detected in hosts that span the eukaryotic tree of life. But surprisingly, such viruses have not been definitively found in Kingdom Fungi, though earlier genomic and metagenomic work suggests putative associations. Here we report both "viral fossils" and active infection by giant viruses in fungi, particularly in the zoosporic phyla Blastocladiomycota and Chytridiomycota. The recovered viral assemblies span up to 350 kb, encode over 300 genes, and form a monophyletic family-level clade within the Nucleocytoviricota related to orders Imitervirales and Algavirales, which we name Mycodnaviridae. We observed variation in infection status among the isolates including apparent active infection and transcriptionally suppressed states, suggesting that viral activation may be constrained to certain life stages of the host. Our experimental findings add to the limited natural virus-host systems available in culture for the study of giant viruses and expand the known host range of Nucleocytoviricota into a new kingdom that contains many model species. Mycodnaviridae have a global distribution, which invites inquiry into the implications of these infections for host traits, host genome evolution, and the metabolic impacts on ecosystems.

Giant Viruses↗
PubMed2006

Synthesis and anti-HIV activity of D- and L-thietanose nucleosides.

Various D- and L-thietanose nucleosides were synthesized from D- and L-xylose. The four-membered thietane ring was efficiently synthesized by the cyclization of 1-thioacetyl-3-mesylate (4/38) under basic conditions. Condensation with various heterocyclic bases was conducted via Pummerer-type rearrangement to afford various nucleoside derivatives. Among the synthesized nucleosides, D-uridine (23), D-cytidine (24), D-5-fluorocytidine (25), and L-cytidine (52) analogues showed moderate anti-HIV activity, with EC50 = 6.9, 1.3, 5.8, and 14.1 microM, respectively. However, these four nucleoside analogues are cytotoxic in peripheral blood mononuclear and CEM cells. The other nucleosides are neither active nor cytotoxic. Interestingly, the oxetanocin A analogue 33 was not active. Comparison of the minimized reverse transcriptases (RTs) complexed with the corresponding triphosphates of the cytidine analogue 24 and the adenosine analogue 33 by molecular modeling studies showed that there is no difference in the binding mode of the triphosphate of the cytidine analogue 24 to the active site of HIV-1 RT from that of the triphosphate of the adenosine analogue 33. Modeling studies on the initial monophosphorylation step by deoxycytidine kinase showed that the catalytic efficiency of phosphorylation through a nucleophilic attack of the 4'-hydroxyl group of thietanose on the gamma-phosphate of ATP is diminished in the case of L-cytidine analogue (52) due to the increased distance between the 4'-hydroxyl group and the gamma-phosphate.

Adenine↗
PubMed2005

6-Benzylthioinosine analogues: promising anti-toxoplasmic agents as inhibitors of the mammalian nucleoside transporter ENT1 (es).

Certain 6-benzylthioinosine analogues have been identified as potential chemotherapeutic agents against Toxoplasma gondii in cell culture and animal models. These compounds are selectively transported and metabolized by toxoplasma infected, but not uninfected, cells. In sharp contrast to mammalian nucleoside transporters, the toxoplasma adenosine/purine transporter (TgAT) allows the transport of these 6-benzylthioinosine analogues into infected cells. After entering the infected cell, these compounds act as subversive substrates for toxoplasma, but not the host, adenosine kinase (EC.2.7.1.20). Hence, 6-benzylthioinosine analogues become toxic to toxoplasma infected cells, but not uninfected host cells or animals. The basis for the lack of uptake of the anti-toxoplasmic 6-benzylthioinosines by uninfected host cells is currently unknown. These anti-toxoplasmic 6-benzylthioinosines may not be substrates for the mammalian nucleoside transporters or they may act as inhibitors of these transporters. Previous studies have shown that some 6-benzylthioinosines are inhibitors of the mammalian nucleoside transporter ENT1 (es). Therefore, we examined the efficacy of promising anti-toxoplasmic 6-benzylthioinosines as inhibitors of ENT1 (es) in an effort to elucidate the basis for the lack of uptake of anti-toxoplasmic 6-benzylthioinosines by uninfected host cells. The results showed that these compounds are inhibitors of ENT1 (es). In general, electron-withdrawing substituents at the ortho, meta or para positions of the benzyl ring improved binding. The most potent inhibitors identified were m- and p-nitro-6-benzylthioinosine, which had K(i) values in the subnanomolar range. Therefore, anti-toxoplasmic 6-benzylthioinosines are not only selectively toxic to parasites and parasite infected cells, they are also inhibitors of nucleoside transport in host cells. This inhibition of the host nucleoside transport is an added advantage for these 6-benzylthioinosine analogues as anti-toxoplasmic agents. Inhibitors of nucleoside transport in mammalian cells can selectively protect the host from the toxicity of toxic purine nucleosides that may be used in future combination therapy against toxoplasmosis or from metabolites of the 6-benzylthioinosine analogues that may be released by the destruction of infected cells. These findings further advance the rationale for developing 6-benzylthioinosine analogues as selective therapeutic agents for the treatment of toxoplasmosis.

Animals↗
PubMed2005

Anti-HIV activity of (-)-(2R,4R)-1- (2-hydroxymethyl-1,3-dioxolan-4-yl)-thymine against drug-resistant HIV-1 mutants and studies of its molecular mechanism.

(-)-(2R,4R)-1-(2-Hydroxymethyl-1,3-dioxolan-4-yl)thymine (DOT) is the first thymidine kinase-activated nucleoside that is significantly active against all of the clinically significant NRTI-resistant HIV-1 mutants, including AZT (D67N/K70R/T215Y/K219Q), Tenofovir (K65R), and Lamivudine (M184V). To understand the molecular mechanism of drug resistance and the antiviral activity of DOT against drug-resistant RTs, molecular modeling studies of DOT-TP complexed with the wild-type (WT) and mutated RT were conducted. The key reason for this interesting antiviral activity profile is the presence of a dioxolane ring.

Anti-HIV Agents↗
PubMed2005

6-Benzylthioinosine analogues as subversive substrate of Toxoplasma gondii adenosine kinase: activities and selective toxicities.

Toxoplasma gondii adenosine kinase (EC.2.7.1.20) is the major route of adenosine metabolism in this parasite. The enzyme is significantly more active than any other enzyme of the purine salvage in T. gondii and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Certain 6-substituted purine nucleosides act as subversive substrates of T. gondii, but not the human, adenosine kinase. Therefore, these compounds are preferentially metabolized to their respective nucleotides and become selectively toxic against the parasites but not their host. Herein, we report the testing of newly synthesized 6-benzylthioinosine analogues with various substituents on the phenyl ring of their benzyl group as subversive substrates of T. gondii adenosine kinases. The binding affinity of these compounds to T. gondii adenosine kinase and their efficacy as antitoxoplasmic agents varied depending on the nature and position of the various substituents on the phenyl ring of their benzyl group. p-Cyano-6-benzylthioinosine and 2,4-dichloro-6-benzylthioinosine were the best ligands. In general, analogues with substitution at the para position of the phenyl ring were better ligands than those with the same substitutions at the meta or ortho position. The better binding of the para-substituted analogues is attributed to the combined effect of hydrophobic as well as van der Waals interactions. The 6-benzylthioinosine analogues were devoid of host-toxicity but all showed selective anti-toxoplasmic effect in cell culture and animal models. These results further confirm that toxoplasma adenosine kinase is an excellent target for chemotherapy and that 6-substituted purine nucleosides are potential selective antitoxoplasmic agents.

Adenosine Kinase↗
PubMed2004

Molecular mechanisms of adefovir sensitivity and resistance in HBV polymerase mutants: a molecular dynamics study.

Molecular modeling studies of adefovir diphosphate with the wild type and the mutant HBV polymerase-DNA complex demonstrated that the increase in adefovir sensitivity toward HBV polymerase mutants (rtL180M, rtM204V/I, rtL180M-M204V/I) is a result of increased van der Waals interaction and is supplemented by the decreased affinity of natural substrate toward the mutant HBV polymerase. In the case of rtN236T mutant, loss of two hydrogen bonds accompanied by significant decrease in electrostatic interactions is observed, which explains the observed decrease in drug sensitivity and binding affinity of adefovir diphosphate toward the rtN236T mutant HBV polymerase.

Adenine↗
PubMed2004

Synthesis, biological activity and molecular modeling of 6-benzylthioinosine analogues as subversive substrates of Toxoplasma gondii adenosine kinase.

Toxoplasma gondii is the most common cause of secondary CNS infections in immunocompromised persons such as AIDS patients. The major route of adenosine metabolism in T. gondii is direct phosphorylation to adenosine 5'-monophosphate (AMP) catalyzed by the enzyme adenosine kinase (EC 2.7.1.20). Adenosine kinase in T. gondii is significantly more active than any other purine salvage enzyme in this parasite and has been established as a potential chemotherapeutic target for the treatment of toxoplasmosis. Subversive substrates of T. gondii,but not the human, adenosine kinase are preferentially metabolized to their monophosphorylated forms and become selectively toxic to the parasites but not their host. 6-Benzylthioinosine (BTI) was identified as an excellent subversive substrate of T. gondii adenosine kinase. Herein, we report the synthesis of new analogues of BTI as subversive substrates for T. gondii adenosine kinase. These new subversive substrates were synthesized starting from tribenzoyl protected d-ribose. To accomplish the lead optimization process, a divergent and focused combinatorial library was synthesized using a polymer-supported trityl group at the 5'-position. The combinatorial library of 20 compounds gave several compounds more active than BTI. Structure-activity relationship studies showed that substitution at the para position plays a crucial role. To investigate the reasons for this discrimination, substrates with different substituents at the para position were studied by molecular modeling using Monte Carlo Conformational Search followed by energy minimization of the enzyme-ligand complex.

Adenosine Kinase↗
PubMed2004

Subtrochanteric fracture managed by intramedullary nail in a patient with pycnodysostosis.

A rare case of a 54-year-old man with pycnodysostosis having subtrochanteric fracture of right femur is being reported. This patient had this fracture after a trivial fall while walking. He had typical facial features, short stature, open fontenella, short stubby hands, high arched furrowed palate and radiological features including open cranial sutures, obtuse angle of mandible, dysplasia of lower end of radius and ulna, notching of lumbar vertebra and generalized skeletal sclerosis. The fracture was treated with an intramedullary nail; the surgery was quite a tedious procedure where we faced per-operative difficulty in reaming. The fracture united in 12 weeks. Extramedullary osteosynthesis might offer a better alternative in such patients as marrow is narrow but healing is normal.

Bone Nails↗
PubMed2002

Role of norepinephrine in the regulation of rapid eye movement sleep.

Sleep and wakefulness are instinctive behaviours that are present across the animal species. Rapid eye movement (REM) sleep is a unique biological phenomenon expressed during sleep. It evolved about 300 million years ago and is noticed in the more evolved animal species. Although it has been objectively identified in its present characteristic form about half a century ago, the mechanics of how REM is generated, and what happens upon its loss are not known. Nevertheless, extensive research has shown that norepinephrine plays a crucial role in its regulation. The present knowledge that has been reviewed in this manuscript suggests that neurons in the brain stem are responsible for controlling this state and presence of excess norepinephrine in the brain does not allow its generation. Furthermore, REM sleep loss increases levels of norepinephrine in the brain that affects several factors including an increase in Na-K ATPase activity. It has been argued that such increased norepinephrine is ultimately responsible for REM sleep deprivation, associated disturbances in at least some of the physiological conditions leading to alteration in behavioural expression and settling into pathological conditions.

Humans↗